Fused heterocyclic compound

ABSTRACT

The present invention relates to a compound represented by the formula: 
     
       
         
         
             
             
         
       
     
     wherein W is C(R 1 ) or N, each A is an optionally substituted aryl group or a heteroaryl group, X 1  is —NR 3 —Y 1 —, —O—, —S—, —SO—, —SO 2 — or —CHR 3 — wherein R 3  is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R 3  is optionally bonded to A to form an optionally substituted ring structure, R 1  is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, R 2  is a hydrogen atom or optionally substituted group bonded via a carbon atom or a sulfur atom, or R 1  and R 2 , or R 2  and R 3  are optionally bonded to form an optionally substituted ring structure, or a salt thereof, and a tyrosine kinase inhibitor or an agent for the prophylaxis or treatment of cancer, which contains this compound or a prodrug thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Division of application Ser. No. 10/592,812, filedSep. 14, 2006, which is a U.S. National Stage of PCT/JP2005/010451,filed Jun. 1, 2005, which applications are incorporated herein byreference.

TECHNICAL FIELD

The present invention relates to a fused pyrimidine compound having agrowth factor receptor tyrosine kinase inhibitory activity, which isuseful for the prophylaxis or treatment of cancer, a production methodthereof and use thereof.

BACKGROUND ART

The gene of cell growth factor and growth factor receptor is called aprotooncogene and plays a key role in the pathology of human tumor. Theepithelial cell growth factor receptor family (erbB) includes EGFR,HER2, HER3 and HER4, which are type I receptor type tyrosine kinases.These erbB family express in various cell groups, and are deeplyinvolved in the control of the growth and differentiation of cells andthe control of suppression of cell death (apoptosis suppression). Forexample, high expression of EGFR and HER2, and homeostatic activation ofreceptors are empirically known to transform cells.

It is also known that high expression and simultaneous expression ofeach of these receptors are poor prognostic factors in various cancerpatients.

These receptors are bound with many peptide ligands such as EGF, TGFαand the like, and binding of the ligand promotes homo- orheterodimerization of the receptors. This induces increase of kinaseactivity from self-phosphorylation or transphosphorylation of thereceptors, and causes activation of downstream signaling pathway (MAPK,Akt) via a protein bound with a particular phosphorylated tyrosineresidue. This is the mechanism of the receptor activity of theabove-mentioned cell growth, differentiation, cell death suppression andthe like, which is considered to be responsible for the high expressionof receptor in cancer and malignant degeneration of cancer due totopical increase in the ligand concentration.

Many cancers are associated with the high expression of EGFR or HER2.For example, breast cancer (20-30%), ovarian cancer (20-40%), non-smallcell lung cancer (30-60%), colorectal cancer (40-80%), prostate cancer(10-60%), bladder cancer (30-60%), kidney cancer (20-40%) and the likecan be mentioned. Moreover, receptor expression and prognosis arecorrelated, and receptor expression is a poor prognostic factor inbreast cancer, non-small cell lung cancer and the like.

In recent years, clinical use of a humanized anti-HER2 antibody(Trastuzumab) against HER2 highly expressing breast cancer, clinicaltrial of anti-EGFR antibody and clinical trials of several low molecularweight receptor enzyme inhibitors have demonstrated a potential of thesedrugs against HER2 or EGFR for therapeutic drugs for cancer. While thesedrugs show a tumor growth inhibitory action in clinical and non-clinicaltrials, they are known to induce inhibition of receptor enzyme activityand suppression of downstream signaling pathway. Therefore, a compoundinhibiting EGFR or HER2 kinase, or inhibiting activation of EGFR or HER2kinase is effective as a therapeutic drug for cancer.

As a compound that inhibits receptor type tyrosine kinases representedby HER2/EGFR kinase, fused heterocyclic compounds (e.g., WO97/13771,WO98/02437, WO00/44728), quinazoline derivatives (e.g., WO02/02552,WO01/98277, WO03/049740, WO03/050108), thienopyrimidine derivatives(e.g., WO03/053446), aromatic azole derivatives (e.g., WO98/03648,WO01/77107, WO03/031442) and the like are known; however, there is noHER2 kinase inhibitory substance to the present that has been marketedas a therapeutic drug for cancer.

As to pyrrolo[3,2-d]pyrimidine derivatives, the following compounds areknown as compounds having a cell growth inhibitory activity (Khim.-Farm.Zh., 1982, 16, 1338-1343; Collect. Czech. Chem. Commun., 2003, 68,779-791).

As a compound having a receptor type tyrosine kinase activity, thefollowing pyrrolo[3,2-d]pyrimidine derivative is known (WO96/40142,WO98/23613).

Furthermore, as to pyrazolo[4,3-d]pyrimidine derivatives,3,5,7-trisubstituted pyrazolo[4,3-d]pyrimidine derivatives are known ascompounds having a CDK inhibitory action, a cell growth inhibitoryaction and/or an apoptosis inducing action (EP-A-1348707), and3-isopropylpyrazolo[4,3-d]pyrimidine derivatives are known as compoundshaving a CDK1/cyclin B inhibitory activity (Bioorganic & MedicinalChemistry Letters, 2003, 13, 2989-2992). Furthermore, synthesis of3-methylpyrazolo[4,3-d]pyrimidine derivatives has been reported (TheJournal of Organic Chemistry, 1956, 21, 833-836).

DISCLOSURE OF THE INVENTION

The present invention aims at providing a compound having a superiortyrosine kinase inhibitory action, which is low toxic and highlysatisfactory as a pharmaceutical product.

The present inventors have conducted intensive studies and found that acompound represented by the following formula (I) and a salt thereof(sometimes to be referred to as compound (I) in the presentspecification) have a superior tyrosine kinase inhibitory action.Further studies have resulted in the completion of the presentinvention.

Accordingly, the present invention provides

[1] a compound represented by the formula:

wherein W is C(R¹) or N,A is an optionally substituted aryl group or an optionally substitutedheteroaryl group,

X¹ is —NR³—Y¹—, —O—, —S—, —SO—, —SO₂— or —CHR³—

wherein R³ is a hydrogen atom or an optionally substituted aliphatichydrocarbon group, or R³ is optionally bonded to a carbon atom or ahetero atom on the aryl group or the heteroaryl group represented by Ato form an optionally substituted ring structure, andY¹ is a single bond or an optionally substituted C₁₋₄ alkylene or anoptionally substituted —O—(C₁₋₄ alkylene)-,R¹ is a hydrogen atom or an optionally substituted group bonded via acarbon atom, a nitrogen atom or an oxygen atom, and R² is a hydrogenatom or an optionally substituted group bonded via a carbon atom or asulfur atom, orR¹ and R², or R² and R³ are optionally bonded to form an optionallysubstituted ring structure, provided that the compounds represented bythe formulas

are excluded, or a salt thereof,[2] a prodrug of the compound of the above-mentioned [1],[3] the compound of the above-mentioned [1], wherein W is C(R¹),[4] the compound of the above-mentioned [3], wherein A is an aryl groupsubstituted by a group of the formula —Y²—B and optionally furthersubstituted, wherein Y² is a single bond, —O—, —O—(C₁₋₃ alkylene)-, —NH—or —S—, and B is an aryl group, a heterocyclic group, a C₃₋₈ cycloalkylgroup, a carbamoyl group, a ureido group, a C₆₋₁₈ aryl-carbonyl group ora C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group, each of which is optionallysubstituted,[5] the compound of the above-mentioned [3], wherein R¹ is a group ofthe formula —X²—R⁴ wherein X² is a single bond, —NH— or —O—, and R⁴ is ahydrogen atom, a cyano group, or a C₁₋₈ alkyl group, a C₂₋₈ alkenylgroup, a C₂₋₈ alkynyl group, a carbamoyl group, a C₁₋₈ alkyl-carbonylgroup, a C₃₋₈ cycloalkyl group, a C₆₋₁₈ aryl group, a C₆₋₁₈ aryl-C₁₋₄alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈ aryl-C₁₋₄alkyl-carbonyl group, a heterocyclic group, a heterocycle-C₁₋₄ alkylgroup, a heterocycle-carbonyl group or a heterocycle-C₁₋₄ alkyl-carbonylgroup, each of which is optionally substituted,[6] the compound of the above-mentioned [3], wherein R² is a hydrogenatom or a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynyl group,a carbamoyl group, a C₁₋₈ alkyl-carbonyl group, a C₁₋₈ alkylsulfonylgroup, a C₃₋₈ cycloalkyl group, a C₆₋₁₈ aryl group, a C₆₋₁₈ aryl-C₁₋₁₄alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈ aryl-C₁₋₄alkyl-carbonyl group, a C₆₋₁₈ aryl-sulfonyl group, a heterocyclic group,a heterocycle-C₁₋₄ alkyl group, a heterocycle-carbonyl group or aheterocycle-C₁₋₄ alkyl-carbonyl group, each of which is optionallysubstituted,[7] the compound of the above-mentioned [3], wherein X¹ is —NR³— whereinR³ is a hydrogen atom or an optionally substituted aliphatic hydrocarbongroup,[8] the compound of the above-mentioned [3], wherein A is an aryl groupsubstituted by a group of the formula —Y²—B and optionally furthersubstituted, wherein Y² is a single bond, —O—, —O—(C₁₋₃ alkylene)-, —NH—or —S—, and B is an aryl group, a heterocyclic group, a C₃₋₈ cycloalkylgroup, a carbamoyl group, a ureido group, a C₆₋₁₈ aryl-carbonyl group ora C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group, each of which is optionallysubstituted;R¹ is a group of the formula —X²—R⁴ wherein X² is a single bond, —NH— or—O—, and R⁴ is a hydrogen atom, a cyano group, or a C₁₋₈ alkyl group, aC₂₋₈ alkenyl group, a C₂₋₈ alkynyl group, a carbamoyl group, a C₁₋₈alkyl-carbonyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₈ aryl group, aC₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈aryl-C₁₋₄ alkyl-carbonyl group, a heterocyclic group, a heterocycle-C₁₋₄alkyl group, a heterocycle-carbonyl group or a heterocycle-C₁₋₄alkyl-carbonyl group, each of which is optionally substituted;R² is a hydrogen atom or a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, aC₂₋₈ alkynyl group, a carbamoyl group, a C₁₋₈ alkyl-carbonyl group, aC₁₋₈ alkylsulfonyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₈ aryl group, aC₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈aryl-C₁₋₄ alkyl-carbonyl group, a C₆₋₁₈ aryl-sulfonyl group, aheterocyclic group, a heterocycle-C₁₋₄ alkyl group, aheterocycle-carbonyl group or a heterocycle-C₁₋₄ alkyl-carbonyl group,each of which is optionally substituted; andX¹ is —NR³— wherein R³ is a hydrogen atom or an optionally substitutedaliphatic hydrocarbon group,[9] the compound of the above-mentioned [1], wherein W is N,[10] the compound of the above-mentioned [9], wherein A is an aryl groupsubstituted by a group of the formula —Y²—B and optionally furthersubstituted, wherein Y² is a single bond, —O—, —O—(C₁₋₃ alkylene)-, —NH—or —S—, and B is an aryl group, a heterocyclic group, a C₃₋₈ cycloalkylgroup, a carbamoyl group, a ureido group, a C₆₋₁₈ aryl-carbonyl group ora C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group, each of which is optionallysubstituted,[11] the compound of the above-mentioned [9], wherein R² is a hydrogenatom or a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynyl group,a carbamoyl group, a C₁₋₈ alkyl-carbonyl group, a C₁₋₈ alkylsulfonylgroup, a C₃₋₈ cycloalkyl group, a C₆₋₁₈ aryl group, a C₆₋₁₈ aryl-C₁₋₄alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈ aryl-C₁₋₄alkyl-carbonyl group, a C₆₋₁₈ aryl-sulfonyl group, a heterocyclic group,a heterocycle-C₁₋₄ alkyl group, a heterocycle-carbonyl group or aheterocycle-C₁₋₄ alkyl-carbonyl group, each of which is optionallysubstituted,[12] the compound of the above-mentioned [9], wherein X¹ is —NR³—wherein R³ is a hydrogen atom or an optionally substituted aliphatichydrocarbon group,[13] the compound of the above-mentioned [9], wherein X¹ is —NR³—wherein R³ is a hydrogen atom or an optionally substituted aliphatichydrocarbon group;A is an aryl group substituted by a group of the formula —Y²—B andoptionally further substituted, wherein Y² is a single bond, —O—,—O—(C₁₋₃ alkylene)-, —NH— or —S—, and B is an aryl group, a heterocyclicgroup, a C₃₋₈ cycloalkyl group, a carbamoyl group, a ureido group, aC₆₋₁₈ aryl-carbonyl group or a C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group,each of which is optionally substituted;R² is a hydrogen atom or a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, aC₂₋₈ alkynyl group, a carbamoyl group, a C₁₋₈ alkyl-carbonyl group, aC₁₋₈ alkylsulfonyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₈ aryl group, aC₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈aryl-C₁₋₄ alkyl-carbonyl group, a C₆₋₁₈ aryl-sulfonyl group, aheterocyclic group, a heterocycle-C₁₋₄ alkyl group, aheterocycle-carbonyl group or a heterocycle-C₁₋₄ alkyl-carbonyl group,each of which is optionally substituted,[14] the compound of the above-mentioned [9], wherein X¹ is —NR³—;A is an aryl group substituted by a group of the formula —Y²—B andoptionally further substituted, wherein Y² is a single bond, —O—,—O—(C₁₋₃ alkylene)-, —NH— or —S—, and B is an aryl group, a heterocyclicgroup, a C₃₋₈ cycloalkyl group, a carbamoyl group, a ureido group, aC₆₋₁₈ aryl-carbonyl group or a C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group,each of which is optionally substituted; andR² and R³ are bonded to form an optionally substituted ring structure,[15] a compound represented by the formula:

wherein R^(1a) is a hydrogen atom or an optionally substituted groupbonded via a carbon atom, a nitrogen atom or an oxygen atom,R^(2a) is an optionally substituted group bonded via a carbon atom or asulfur atom, orR^(1a) and R^(2a), or R^(2a) and R^(3a) are optionally bonded to form anoptionally substituted ring structure,R^(3a) is a hydrogen atom or an optionally substituted aliphatichydrocarbon group, orR^(3a) is optionally bonded to a carbon atom of the adjacent phenylgroup to form an optionally substituted ring structure,B^(a) is an optionally substituted benzene ring, andC^(a) is an optionally substituted —C₆₋₁₈ aryl group, or a salt thereof,[16] a compound represented by the formula:

wherein R^(1b) is a hydrogen atom or an optionally substituted groupbonded via a carbon atom, a nitrogen atom or an oxygen atom,R^(2b) is an optionally substituted group bonded via a carbon atom or asulfur atom, orR^(1b) and R^(2b), or R^(2b) and R^(3b) are optionally bonded to form anoptionally substituted ring structure,R^(3b) is a hydrogen atom or an optionally substituted aliphatichydrocarbon group, orR^(3b) is optionally bonded to a carbon atom of the adjacent phenylgroup to form an optionally substituted ring structure,B^(b) is an optionally substituted benzene ring,C^(b) is an optionally substituted C₆-18 aryl group, andZ^(b) is an optionally substituted C₁₋₃ alkylene group, or a saltthereof,[17] a compound represented by the formula:

wherein R^(1c) is a hydrogen atom or an optionally substituted groupbonded via a carbon atom, a nitrogen atom or an oxygen atom,R^(2c) is an optionally substituted group bonded via a carbon atom or asulfur atom, orR^(1c) and R^(2c), or R^(2c) and R^(3c) are optionally bonded to form anoptionally substituted ring structure,R^(3c) is a hydrogen atom or an optionally substituted aliphatichydrocarbon group, orR^(3c) is optionally bonded to a carbon atom of the adjacent phenylgroup to form an optionally substituted ring structure,B^(c) is an optionally substituted benzene ring, andC^(c) is an optionally substituted heterocyclic group, or a saltthereof,[18] a compound represented by the formula:

wherein R^(1d) is a hydrogen atom or an optionally substituted groupbonded via a carbon atom, a nitrogen atom or an oxygen atom,R^(2d) is an optionally substituted group bonded via a carbon atom or asulfur atom, orR^(1d) and R^(2d), or R^(2d) and R^(3d) are optionally bonded to form anoptionally substituted ring structure,R^(3d) is a hydrogen atom or an optionally substituted aliphatichydrocarbon group, orR^(3d) is optionally bonded to a carbon atom of the adjacent phenylgroup to form an optionally substituted ring structure,B^(d) is an optionally substituted benzene ring,C^(d) is an optionally substituted heterocyclic group, andZ^(d) is an optionally substituted C₁₋₃ alkylene group, or a saltthereof,[19] a compound represented by the formula:

wherein R^(2e) is an optionally substituted group bonded via a carbonatom or a sulfur atom, orR^(2e) and R^(3e) are optionally bonded to form an optionallysubstituted ring structure,R^(3e) is a hydrogen atom or an optionally substituted aliphatichydrocarbon group, orR^(3e) is optionally bonded to a carbon atom of the adjacent phenylgroup to form an optionally substituted ring structure,B^(e) is an optionally substituted benzene ring, andC^(e) is an optionally substituted C₆₋₁₈ aryl group, or a salt thereof,[20] a compound represented by the formula:

wherein R^(2f) is an optionally substituted group bonded via a carbonatom or a sulfur atom, orR^(2f) and R^(3f) are optionally bonded to form an optionallysubstituted ring structure,R^(3f) is a hydrogen atom or an optionally substituted aliphatichydrocarbon group, orR^(3f) is optionally bonded to a carbon atom of the adjacent phenylgroup to form an optionally substituted ring structure,B^(f) is an optionally substituted benzene ring,C^(f) is an optionally substituted C₆₋₁₈ aryl group, andZ^(f) is an optionally substituted C₁₋₃ alkylene group, or a saltthereof,[21] a compound represented by the formula:

wherein R^(2g) is an optionally substituted group bonded via a carbonatom or a sulfur atom, orR^(2g) and R^(1g) are optionally bonded to form an optionallysubstituted ring structure,R^(3g) is a hydrogen atom or an optionally substituted aliphatichydrocarbon group, orR^(3g) is optionally bonded to a carbon atom of the adjacent phenylgroup to form an optionally substituted ring structure,B^(g) is an optionally substituted benzene ring, andC^(g) is an optionally substituted heterocyclic group, or a saltthereof,[22] (i)2-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol,(ii)2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol,(iii)N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxy-3-methylbutanamide,(iv)N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide,(v)N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-methyl-2-(methylsulfonyl)propanamide,(vi)5-{2-[2-(tert-butylsulfonyl)ethoxy]ethyl}-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine,(vii)2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}acetamide,(viii)N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-2-(methylsulfonyl)acetamide,or(ix)N-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide,or a salt of any of them,[23] a method of producing a compound represented by the formula:

wherein each symbol is as defined in the above-mentioned [1], or a saltthereof, which comprises reacting a compound represented by the formula:

wherein L is a leaving group, and other symbols are as defined in theabove-mentioned [1], or a salt thereof with a compound represented bythe formula:

G-X¹-A  (III)

wherein G is a hydrogen atom or a metal atom, and other symbols are asdefined in the above-mentioned [1], or a salt thereof,[24] a pharmaceutical agent comprising a compound represented by theformula:

wherein W is C(R¹) or N,A is an optionally substituted aryl group or an optionally substitutedheteroaryl group,

X¹ is —NR³—Y¹—, —O—, —S—, —SO—, —SO₂— or —CHR³—

wherein R³ is a hydrogen atom or an optionally substituted aliphatichydrocarbon group, or R³ is optionally bonded to a carbon atom or ahetero atom on the aryl group or the heteroaryl group represented by Ato form an optionally substituted ring structure, andY¹ is a single bond or an optionally substituted C₁₋₄ alkylene or anoptionally substituted —O—(C₁₋₄ alkylene)-,R¹ is a hydrogen atom or an optionally substituted group bonded via acarbon atom, a nitrogen atom or an oxygen atom, and R² is a hydrogenatom or an optionally substituted group bonded via a carbon atom or asulfur atom, orR¹ and R², or R² and R³ are optionally bonded to form an optionallysubstituted ring structure, provided that the compounds represented bythe formulas

are excluded, or a salt thereof, or a prodrug thereof,[25] the pharmaceutical agent of the above-mentioned [24] which is atyrosine kinase inhibitor,[26] the pharmaceutical agent of the above-mentioned [24] which is anagent for the prophylaxis or treatment of cancer,[27] the pharmaceutical agent of the above-mentioned [26] wherein thecancer is breast cancer, prostate cancer, lung cancer, pancreatic canceror kidney cancer,[28] a method for the prophylaxis or treatment of cancer in a mammal,which comprises administering, to said mammal, an effective amount of acompound represented by the formula:

wherein W is C(R¹) or N,A is an optionally substituted aryl group or an optionally substitutedheteroaryl group,

X¹ is —NR³—Y¹—, —O—, —S—, —SO—, —SO₂— or —CHR³—

wherein R³ is a hydrogen atom or an optionally substituted aliphatichydrocarbon group, or R³ is optionally bonded to a carbon atom or ahetero atom on the aryl group or the heteroaryl group represented by Ato form an optionally substituted ring structure, andY¹ is a single bond or an optionally substituted C₁₋₄ alkylene or anoptionally substituted —O—(C₁₋₄ alkylene)-,R¹ is a hydrogen atom or an optionally substituted group bonded via acarbon atom, a nitrogen atom or an oxygen atom, and R² is a hydrogenatom or an optionally substituted group bonded via a carbon atom or asulfur atom, orR¹ and R², or R² and R³ are optionally bonded to form an optionallysubstituted ring structure, provided that the compounds represented bythe formulas

are excluded, or a salt thereof, or a prodrug thereof,[29] use of a compound represented by the formula:

wherein W is C(R¹) or N,A is an optionally substituted aryl group or an optionally substitutedheteroaryl group,

X¹ is —NR³—Y¹—, —O—, —S—, —SO—, —SO₂— or —CHR³—

wherein R³ is a hydrogen atom or an optionally substituted aliphatichydrocarbon group, or R³ is optionally bonded to a carbon atom or ahetero atom on the aryl group or the heteroaryl group represented by Ato form an optionally substituted ring structure, andY¹ is a single bond or an optionally substituted C₁₋₄ alkylene or anoptionally substituted —O—(C₁₋₄ alkylene)-,R¹ is a hydrogen atom or an optionally substituted group bonded via acarbon atom, a nitrogen atom or an oxygen atom, and R² is a hydrogenatom or an optionally substituted group bonded via a carbon atom or asulfur atom, orR¹ and R², or R² and R³ are optionally bonded to form an optionallysubstituted ring structure, provided that the compounds represented bythe formulas

are excluded, or a salt thereof, or a prodrug thereof, for theproduction of an agent for the prophylaxis or treatment of cancer, andthe like.

Furthermore, the present invention provides

[30] the compound of the above-mentioned [15], wherein R², is(i) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynyl group, aC₁₋₈ alkyl-carbonyl group, a C₁₋₈ alkylsulfonyl group, a C₃₋₈ cycloalkylgroup, a C₆₋₁₈ aryl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈aryl-carbonyl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group, a C₆₋₁₈aryl-sulfonyl group, a heterocyclic group, a heterocycle-C₁₋₄ alkylgroup, a heterocycle-carbonyl group or a heterocycle-C₁₋₄ alkyl-carbonylgroup, each of which is optionally substituted by 1 to 5 substituentsselected from the group (substituent group T) consisting of(a) halogen,(b) oxo,(c) optionally halogenated C₁₋₄ alkyl,(d) —(CH₂)_(m)-Q,(e) —(CH₂)_(m)-Z¹- (optionally halogenated C₁₋₄ alkyl),(f) —(CH₂)_(m)-Z¹-C₃₋₈ cycloalkyl,(g) —(CH₂)_(m)-Z²-(CH₂)_(n)-Q,(h) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹- (optionally halogenated C₁₋₄ alkyl),(i) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹-C₃₋₈ cycloalkyl,(j) —(CH₂)_(m)-Z¹- (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom),(k) —(CH₂)_(m)-Z²-C₁₋₄ alkoxy, and(l) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹-(CH₂)_(n)-Z¹-C₁₋₄ alkylwherein m is an integer of 0 to 4,n is an integer of 1 to 4,Q is hydroxy, carboxy, cyano, nitro, —NR⁶R⁷, —CONR⁶R⁷, —OCONH₂ or—SO₂NR⁶R⁷,Z¹ is —O—, —CO—, —C(OH)R—, —C(═N—OR⁸)—, —S—, —SO—, —SO₂—, —N(COR⁸)—,—N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—OC—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—, —NR⁸—CO₂—,—NR⁸—CO—NH—, —NR⁸—SO₂—, or —NR⁸—C(═NH)—NH—,Z² is —O—, —CO—, —C(OH)R⁸—, —C(═N—OR⁸)—, —S—, —SO—, —SO₂—, —NR⁸—,—N(COR⁸)—, —N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—,—NR⁸—CO₂—, —NR⁸—CO—NH—, —NR⁸—C(═NH)—NH—, —NR⁸—SO₂—, or —SO₂—NR(CH₂)_(m) and (CH₂)_(n) are optionally substituted by 1 to 5substituents selected from halogen, optionally halogenated C₁₋₄ alkyland hydroxy, and when m or n is not less than 2, a subset —CH₂CH₂— of(CH₂)_(m) and (CH₂) is optionally replaced by —CH═CH— or —C≡C—,R⁶ and R⁷ are the same or different and each is a hydrogen atom or aC₁₋₄ alkyl group, or R⁶ and R⁷ are bonded to form, together with anitrogen atom, a 3- to 8-membered saturated or unsaturated aliphaticheterocyclic group,R⁸ is a hydrogen atom or a C₁₋₄ alkyl group, andR⁹ is a C₁₋₄ alkyl group, or(ii) a carbamoyl group optionally having 1 or 2 C₁₋₈ alkyl group(s)optionally substituted by substituent(s) selected from substituent groupT,wherein said carbamoyl group has two substituents, which optionallyform, together with the adjacent nitrogen atom, a 3- to 8-memberedsaturated or unsaturated aliphatic heterocyclic group optionallysubstituted by substituent(s) selected from substituent group T,[31] the compound of the above-mentioned [15], whereinB^(a) is a benzene ring optionally substituted by 1 to 4 substituentsselected from halogen, C₁₋₄ alkyl, hydroxy-C₁₋₄ alkyl and C₁₋₄ alkyloxy;C^(a) is a phenyl group optionally substituted by 1 to 5 substituentsselected from(i) halogen,(ii) optionally halogenated C₁₋₄ alkyl,(iii) hydroxy-C₁₋₄ alkyl,(iv) heterocycle-C₁₋₄ alkyl (preferably, 5- to 8-memberedheterocycle-C₁₋₄ alkyl, said 5- to 8-membered heterocycle has 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and anoptionally oxidized sulfur atom, such as imidazolyl, triazolyl and thelike),(v) optionally halogenated C₁₋₄ alkyloxy,(vi) C₁₋₄ alkyl-carbonyl,(vii) cyano,(viii) carbamoyl optionally substituted by C₁₋₈ alkyl, and(ix) C₁₋₄ alkoxy-carbonyl;

R^(1a) is

(i) a hydrogen atom,(ii) a cyano group, or(iii) a C₁₋₄ alkyl group or a C₂₋₄ alkenyl group, each of which isoptionally substituted by —NR⁸—CO—(CH₂)_(n)—NR⁶R⁷wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or differentand each is a hydrogen atom or a C₁₋₄ alkyl group, R⁸ is a hydrogen atomor a C₁₋₄ alkyl group, and when n is not less than 2, a subset —CH₂CH₂—of (CH₂)_(n) is optionally replaced by —CH═CH—; andR^(2a) is a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group or a C₂₋₈ alkynylgroup, each of which is optionally substituted by substituent(s)selected from(a) hydroxy,(b) carboxy,(c) cyano,(d) optionally halogenated C₁₋₄ alkyloxy,(e) —O—(CH₂)_(n)—OH,(f) —O—(CH₂)_(n)—O—CO—NH₂,(g) —O—(CH₂)_(n)—O— (optionally halogenated C₁₋₄ alkyl),(h) —O—(CH₂)—SO₂— (optionally halogenated C₁₋₄ alkyl),(i) —O—(CH₂)_(n)—SO₂—C₆₋₁₈ aryl,(j) —O—(CH₂)_(n)—SO₂—(CH₂)_(n)—OH,(k) —O—(CH₂)_(n)—NR⁸—CO—C₁₋₄ alkyl,(l) —O—(CH₂)—NR⁸—CO—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(m) —O—(CH₂)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(n) —CO—NR⁸—(CH₂)_(n)—OH,(o) —CO—NR⁸—(CH₂)—SO₂— (optionally halogenated C₁₋₄ alkyl),(p) —CO—NR⁸—O—C₁₋₄ alkyl,

(q) —NR⁶R⁷,

(r) —NR⁸—(CH₂)_(n)—OH,(s) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(t) —NR⁸—CO— (optionally halogenated C₁₋₄ alkyl),

(u) —NR⁸—CO—(CH₂)—OH, (v) —NR⁸—CO—(CH₂)—CN,

(w) —NR⁸—CO—(CH₂)_(n)—NR⁶R⁷,(x) —NR⁸—CO—(CH₂)—O—C₁₋₄ alkyl,(y) —NR⁸—CO—(CH₂)—SO— (optionally halogenated C₁₋₄ alkyl),(z) —NR⁸—CO—(CH₂)—SO₂— (optionally halogenated C₁₋₄ alkyl),(aa) —NR⁸—CO—(CH₂)—SO₂—C₃₋₈ cycloalkyl,(bb) —NR⁸—CO—(CH₂)_(n)—NR⁸—SO₂—C₁₋₄ alkyl,(cc) —NR⁸—CO₂—(CH₂)—SO₂—C₁₋₄ alkyl,(dd) —NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(ee) —NR⁸—CO—NH—O—C₁₋₄ alkyl,(ff) —NR⁸—CO—NH—(CH₂)_(n)—O—C₁₋₄ alkyl,(gg) —NR⁸—C(═NH)—NH—C₁₋₄ alkyl,(hh) —NR⁸—SO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,

(ii) —S—(CH₂)—OH,

(jj) —SO—(CH₂)_(n)—OH,(kk) —SO₂—(CH₂)_(n)—OH, and(ll) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—O—C₁₋₄ alkyl,—CO—NH—C₁₋₄ alkyl, —CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂and the like) wherein n is an integer of 1 to 4, R⁶ and R⁷ are the sameor different and each is a hydrogen atom or a C₁₋₄ alkyl group, R⁸ is ahydrogen atom or a C₁₋₄ alkyl group, (CH₂)_(n) are optionallysubstituted by halogenated C₁₋₄ alkyl or hydroxy, and when n is not lessthan 2, a subset —CH₂CH₂— of (CH₂)_(n) is optionally replaced by—CH═CH—;R^(3a) is a hydrogen atom or a C₁₋₆ alkyl group; orR^(1a) and R^(2a) are optionally bonded to form

R^(2a) and R^(3a) are optionally bonded to form C₂₋₄ alkylene optionallysubstituted by an imino group, particularly preferably, R^(2a) is a C₁₋₈alkyl group, a C₂₋₈ alkenyl group or a C₂₋₈ alkynyl group (particularly,a C₁₋₈ alkyl group), each of which is optionally substituted bysubstituent(s) selected from(a) hydroxy,(b) carboxy,(c) cyano,(d) optionally halogenated C₁₋₄ alkyloxy,(e) —O—(CH₂)_(n)—OH (wherein (CH₂)_(n) is optionally substituted byhydroxy),(f) —O—(CH₂)_(n)—O—CO—NH₂,(g) —O—(CH₂)—O— (optionally halogenated C₁₋₄ alkyl),(h) —O—(CH₂)—SO₂— (optionally halogenated C₁₋₄ alkyl),(i) —O—(CH₂)_(n)—SO₂—C₆₋₁₈ aryl,(j) —O—(CH₂)_(n)—SO₂—(CH₂)_(n)—OH,(k) —O—(CH₂)—NR⁸—CO—C₁₋₄ alkyl,(l) —O—(CH₂)_(n)—NR⁸—CO—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(m) —O—(CH₂)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(n) —CO—NR⁸—(CH₂)_(n)—OH,(o) —CO—NR⁸—(CH₂)—SO₂— (optionally halogenated C₁₋₄ alkyl),

-   (p) —CO—NR⁸—O—C₁₋₄ alkyl,

(q) —NR⁶R⁷,

(r) —NR⁸—(CH₂)_(n)—OH,(s) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₁₄ alkyl,(t) —NR⁸—CO— (optionally halogenated C₁₋₄ alkyl),(u) —NR⁸—CO—(CH₂)—OH (wherein (CH₂)_(n) is optionally substituted byoptionally halogenated C₁₋₄ alkyl or hydroxy),(v) —NR⁸—CO—(CH₂)_(n)—CN,(w) —NR⁸—CO—(CH₂)—NR⁶R⁷ (when n is not less than 2, a subset —CH₂CH₂— of(CH₂)_(n) is optionally replaced by —CH═CH—),(x) —NR⁸—CO—(CH₂)—O—C₁₋₄ alkyl,(y) —NR⁸—CO—(CH₂)_(n)—SO— (optionally halogenated C₁₋₄ alkyl),(z) —NR⁸—CO—(CH₂)—SO₂— (optionally halogenated C₁₋₄ alkyl)(wherein (CH₂) is optionally substituted by C₁₋₄ alkyl),(aa) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(bb) —NR⁸—CO—(CH₂)_(n)—NR⁸—SO₂—C₁₋₄ alkyl,(cc) —NR⁸—CO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(dd) —NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(ee) —NR⁸—CO—NH—O—C₁₋₄ alkyl,(ff) —NR⁸—CO—NH(CH₂)_(n)—O—C₁₋₄ alkyl,(gg) —NR⁸—C(═NH)—NH—C₁₋₄ alkyl,(hh) —NR⁸—SO₂—(CH₂)—SO₂—C₁₋₄ alkyl,(ii) —S—(CH₂)_(n)—OH,(jj) —SO—(CH₂)_(n)—OH,(kk) —SO₂—(CH₂)_(n)—OH, and(ll) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—O—C₁₋₄ alkyl,—CO—NH—C₁₋₄ alkyl, —CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂and the like), wherein n is an integer of 1 to 4, R⁶ and R⁷ are the sameor different and each is a hydrogen atom or a C₁₋₄ alkyl group, R⁸ is ahydrogen atom or a C₁₋₄ alkyl group,[32] the compound of the above-mentioned [15], whereinB^(a) is a benzene ring optionally substituted by 1 to 4 substituentsselected from halogen and optionally halogenated C₁₋₄ alkyl;C^(a) is a phenyl group substituted by 1 to 5 substituents selected from(i) halogen,(ii) optionally halogenated C₁₋₄ alkyl,(iii) hydroxy-C₁₋₄ alkyl,(iv) heterocycle-C₁₋₄ alkyl (preferably, 5- to 8-memberedheterocycle-C₁₋₄ alkyl, said 5- to 8-membered heterocycle has 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and anoptionally oxidized sulfur atom, such as imidazolyl and the like),(v) optionally halogenated C₁₋₄ alkyloxy,(vi) cyano, and(vii) carbamoyl optionally substituted by C₁₋₈ alkyl;R^(1a) is a hydrogen atom;R^(2a) is a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group or a C₂₋₈ alkynylgroup, each of which is substituted by substituent(s) selected from(a) hydroxy,(b) optionally halogenated C₁₋₄ alkyloxy,(c) —O—(CH₂)_(n)—OH,(d) —O—(CH₂)_(n)—O—CO—NH₂,(e) —O—(CH₂)_(n)—O—C₁₋₄ alkyl,(f) —O—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(g) —O—(CH₂)_(n)—SO₂—C₆₋₁₈ aryl,(h) —O—(CH₂)_(n)—SO₂—(CH₂)_(n)—OH,(i) —O—(CH₂)_(n)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(j) —CO—NR⁸—(CH₂)_(n)—OH,(k) —CO—NR⁸—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),

(l) —NR⁶R⁷,

(m) —NR⁸—(CH₂)_(n)—OH,(n) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(o) —NR⁸—CO(CH₂)_(n)—OH,(p) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(q) —NR⁸—CO—(CH₂)_(n)—SO— (optionally halogenated C₁₋₄ alkyl),(r) —NR⁸—CO—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(s) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(t) —NR⁸—CO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(u)—NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(v) —NR⁸—SO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(w) —S—(CH₂)_(n)—OH,(x) —SO—(CH₂)_(n)—OH,(y) —SO₂—(CH₂)_(n)—OH, and(z) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—NH—C₁₋₄ alkyl,—CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂ and the like),wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or differentand each is a hydrogen atom or a C₁₋₄ alkyl group, R⁸ is a hydrogen atomor a C₁₋₄ alkyl group, and (CH₂)_(n) is optionally substituted by C₁₋₄alkyl or hydroxy;R^(3a) is a hydrogen atom or a C₁₋₆ alkyl group; orR^(1a) and R^(2a) are optionally bonded to form

R^(2a) and R^(3a) are optionally bonded to form C₂₋₄ alkylene,particularly preferably, R^(2a) is a C₁₋₁₈ alkyl group, a C₂₋₈ alkenylgroup or a C₂₋₈ alkynyl group (particularly, a C₁₋₁₈ alkyl group), eachof which is substituted by substituent(s) selected from (a) hydroxy,(b) optionally halogenated C₁₋₄ alkyloxy,(c) —O—(CH₂)_(n)—OH (wherein (CH₂)_(n) is optionally substituted byhydroxy),(d) —O—(CH₂)_(n)—O—CO—NH₂,(e) —O—(CH₂)_(n)—O—C₁₋₄ alkyl,(f) —O—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(g) —O—(CH₂)_(n)—SO₂—C₆₋₁₈ aryl,(h) —O—(CH₂)_(n)—SO₂—(CH₂)_(n)—OH,(i) —O—(CH₂)_(n)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(j) —CO—NR⁸—(CH₂)_(n)—OH,(k) —CO—NR⁸—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),

(l) —NR⁶R⁷,

(m) —NR⁸—(CH₂)_(n)—OH,(n) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(o) —NR⁸CO—(CH₂)_(n)—OH (wherein CH₂)_(n) is optionally substituted byC₁₋₄ alkyl),(p) —NR⁸—CO—(CH₂)_(n), —O—C₁₋₄ alkyl,(q) —NR⁸—CO—(CH₂)_(n)—SO— (optionally halogenated C₁₋₄ alkyl),(r) —NR⁸—CO—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl)(wherein (CH₂)_(n) is optionally substituted by C₁₋₄ alkyl),(s) —NR⁸—CO—(CH₂)—SO₂—C₃₋₈ cycloalkyl,(t) —NR⁸—CO₂—(CH₂)—SO₂—C₁₋₄ alkyl,(u) —NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(v) —NR⁸—SO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(w) —S—(CH₂)_(n)—OH,(x) —SO—(CH₂)_(n)—OH,(y) —SO₂—(CH₂)_(n)—OH, and(z) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—NH—C₁₋₄ alkyl,—CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂ and the like),wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or differentand each is a hydrogen atom or a C₁₋₄ alkyl group, and R⁸ is a hydrogenatom or a C₁₋₄ alkyl group,[33] the compound of the above-mentioned [31], whereinR^(2a) is (i) a C₅₋₈ alkyl group substituted by hydroxy,(ii) a C₁₋₈ alkyl group substituted by substituent(s) selected from(a) halogenated C₁₋₄ alkyloxy,(b) —O—(CH₂)_(n)—OH,(c) —O—(CH₂)_(n)—O—CO—NH₂,(d) —O—(CH₂)_(n)—O— (optionally halogenated C₁₋₄ alkyl),(e) —O—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(f) —O—(CH₂)_(n)—SO₂—C₆₁₈ aryl,(g) —O—(CH₂)_(n)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl)(h) —CO—NR—(CH₂)_(n)—OH,(i) —CO—NR⁸—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(j) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(k) —NR⁸—CO—(CH₂)_(n)—OH,(l) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(m) —NR⁸—CO—(CH₂)_(n)—SO— (optionally halogenated C₁₋₄ alkyl),(n) —NR⁸—CO—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(o) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(p) —NR⁸—CO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(q) —NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(r) —NR⁸—SO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(s) —S—(CH₂)_(n)—OH,(t) —SO—(CH₂)_(n)—OH,(u) —SO₂—(CH₂)_(n)—OH, and(v) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—NH—C₁₋₄ alkyl,—CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂ and the like),wherein n is an integer of 1 to 4, R⁸ is a hydrogen atom or a C₁₋₄ alkylgroup, and (CH₂)_(n) is optionally substituted by C₁₋₄ alkyl or hydroxy,(iii) a C₂₋₈ alkenyl group optionally substituted by hydroxy, or(iv) a C₂₋₈ alkynyl group optionally substituted by hydroxy,particularly preferably, R^(2a) is (i) a C₅₋₈ alkyl group substituted byhydroxy,(ii) a C₁₋₈ alkyl group substituted by substituent(s) selected from(a) halogenated C₁₋₄ alkyloxy,(b) —O—(CH₂)_(n)—OH (wherein (CH₂)_(n) is optionally substituted byhydroxy),(c) —O—(CH₂)_(n)—O—CO—NH₂,(d) —O—(CH₂)—O— (optionally halogenated C₁₋₄ alkyl),(e) —O—(CH₂)—SO₂— (optionally halogenated C₁₋₄ alkyl),(f) —O—(CH₂)_(n)—SO₂—C₆₋₁₈ aryl,(g) —O—(CH₂)N—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(h) —CO—NR⁸—(CH₂)_(n)—OH,(i) —CO—NR⁸—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(j) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(k) —NR⁸—CO—(CH₂)_(n)—OH (wherein (CH₂)_(n) is optionally substituted byC₁₋₄ alkyl),(l) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(m) —NR⁸—CO—(CH₂)_(n)—SO— (optionally halogenated C₁₋₄ alkyl),(n) —NR⁸—CO—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(wherein (CH₂)_(n) is optionally substituted by C₁₋₄ alkyl),(o) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(p) —NR⁸—CO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(q) —NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(r) —NR⁸—SO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(s) —S—(CH₂)_(n)—OH,(t) —SO—(CH₂)_(n)—OH,(u) —SO₂—(CH₂)_(n)—OH, and(v) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—NH—C₁₋₄ alkyl,—CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂ and the like),wherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group,(iii) a C₂₋₈ alkenyl group optionally substituted by hydroxy, or(iv) a C₂₋₈ alkynyl group optionally substituted by hydroxy,[34] the compound of the above-mentioned [16], whereinR^(2b) is (i) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynylgroup, a C₁₋₈ alkyl-carbonyl group, a C₁₋₈ alkylsulfonyl group, a C₃₋₈cycloalkyl group, a C₆₋₁₈ aryl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl group, aC₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group, aC₆₋₁₈ aryl-sulfonyl group, a heterocyclic group, a heterocycle-C₁₋₄alkyl group, a heterocycle-carbonyl group or a heterocycle-C₁₋₄alkyl-carbonyl group, each of which is optionally substituted by 1 to 5substituents selected from the group (substituent group T) consisting of(a) halogen,(b) oxo,(c) optionally halogenated C₁₋₄ alkyl,(d) —(CH₂)_(m)-Q,(e) —(CH₂)-Z¹- (optionally halogenated C₁₋₄ alkyl),(f) —(CH₂)_(n)-Z¹-C₃₋₈ cycloalkyl,(g) —(CH₂)_(m)-Z²-(CH₂)_(n)-Q,(h) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹- (optionally halogenated C₁₋₄ alkyl),(i) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹-C₃₋₈ cycloalkyl,(j) —(CH₂)_(m)-Z¹- (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom),(k) —(CH₂)_(m)-Z²-C₁₋₄ alkoxy, and(l) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹-(CH₂)_(n)-Z¹-C₁₋₄ alkylwherein m is an integer of 0 to 4, n is an integer of 1 to 4, Q ishydroxy, carboxy, cyano, nitro, —NR⁶R⁷, —CONR⁶R⁷, —OCONH₂ or —SO₂NR⁶R⁷,Z¹ is —O—, —CO—, —C(OH)R⁸—, —C(═N—OR⁸)—, —S—, —SO—, —SO₂—, —N(COR⁸)—,—N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—, —NR⁸—CO₂—,—NR⁸—CO—NH—, —NR⁸—SO₂—, or —NR⁸—C(═NH)—NH—, Z² is —O—, —CO—, —C(OH)R⁸—,—C(═N—OR⁸)—, —S—, —SO—, —SO₂—, —NR⁸—N(COR⁸)—, —N(CO₂R⁹)—, —N(SO₂R⁹)—,—CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—, —NR⁸—CO₂—, —NR⁸—CO—NH—,—NR⁸—C(═NH)—NH—, —NR⁸—SO₂—, or —SO₂—NR⁸—,(CH₂)_(m) and (CH₂)_(n) are optionally substituted by 1 to 5substituents selected from halogen, optionally halogenated C₁₋₄ alkyland hydroxy, and when m or n is not less than 2, a subset —CH₂CH₂— of(CH₂)_(m) and (CH₂)_(n) is optionally replaced by —CH═CH— or —C≡C—,R⁶ and R⁷ are the same or different and each is a hydrogen atom or aC₁₋₄ alkyl group, or R⁶ and R⁷ are bonded to form, together with anitrogen atom, a 3- to 8-membered saturated or unsaturated aliphaticheterocyclic group,R⁸ is a hydrogen atom or a C₁₋₄ alkyl group, and R⁹ is a C₁₋₄ alkylgroup, or(ii) a carbamoyl group optionally having 1 or 2 C₁₋₈ alkyl group(s)optionally substituted by substituent(s) selected from substituent groupT,wherein the carbamoyl group has two substituents, and they optionallyform, together with the adjacent nitrogen atom, a 3- to 8-memberedsaturated or unsaturated aliphatic heterocyclic group optionallysubstituted by substituent(s) selected from substituent group T,[35] the compound of the above-mentioned [16] whereinB^(b) is a benzene ring optionally substituted by halogen;C^(b) is a phenyl group optionally substituted by 1 to 5 substituentsselected from halogen, optionally halogenated C₁₋₄ alkyl and cyano;R^(1b) is (i) a hydrogen atom, or(ii) a C₂₋₄ alkenyl group optionally substituted by hydroxy;

R^(2b) is

(i) a C₁₋₈ alkyl group optionally substituted by substituent(s) selectedfrom(a) halogen,(b) hydroxy,(c) C₁₋₄ alkyloxy,(d) —O—(CH₂)_(n)—OH,(e) —O—(CH₂)_(n)—O—C₁₋₄ alkyl,

(f) —CO—NR⁸—(CH₂)—OH, (g) —NR⁶R⁷, and

(h) —NR⁸—(CH₂)_(n)—OH,wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or differentand each is a hydrogen atom or a C₁₋₄ alkyl group, and R⁸ is a hydrogenatom or a C₁₋₄ alkyl group,(ii) a C₆₋₁₈ aryl-C₁₋₄ alkyl group optionally substituted bysubstituent(s) selected from(a) C₁₋₄ alkyl optionally having hydroxy,(b) carboxy,(c) C₁₋₄ alkoxy-carbonyl,(d) 5- to 8-membered heterocycle-carbonyl having 1 to 3 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom, whichoptionally has substituent(s) selected from hydroxy and C₁₋₄ alkyl, and(e) C₁₋₄ alkyl-carbamoyl optionally having substituent(s) selected fromhydroxy and carbamoyl,(iii) a C₆₋₁₈ aryl-carbonyl group optionally substituted by C₁₋₄ alkoxy,(iv) a C₆₋₁₈ aryl-sulfonyl group optionally substituted by C₁₋₄ alkoxy,or(v) a 5- to 8-membered heterocycle-C₁₋₁₄ alkyl group having 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfuratom, which is optionally substituted by substituent(s) selected from(a) carboxy, and(b) C₁₋₄ alkoxy-carbonyl;R^(3b) is a hydrogen atom or a C₁₋₆ alkyl group; orR^(2b) and R^(3b) are optionally bonded to form C₂₋₄ alkylene; andZ^(b) is a C₁₋₃ alkylene group,[36] the compound of the above-mentioned [16], whereinB^(b) is a benzene ring optionally substituted by halogen;C^(b) is a phenyl group optionally substituted by 1 to 5 substituentsselected from halogen and optionally halogenated C₁₋₄ alkyl;R^(1b) is a hydrogen atom;R^(2b) is a C₁₋₈ alkyl group optionally substituted by substituent(s)selected from (a) hydroxy,

(b) —O—(CH₂)—OH,

(c) —O—(CH₂)_(n)—O—C₁₋₄ alkyl,(d) —CO—NR⁸—(CH₂)_(n)—OH,

(e) —NR⁶R⁷, and

(f) —NR⁸—(CH₂)_(n)—OH,wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or differentand each is a hydrogen atom or a C₁₋₄ alkyl group, and R⁸ is a hydrogenatom or a C₁₋₄ alkyl group;R^(3b) is a hydrogen atom or a C₁₋₆ alkyl group; andZ^(b) is a C₁₋₃ alkylene group,[37] the compound of the above-mentioned [36], whereinB^(b) is a benzene ring optionally substituted by halogen;C^(b) is a phenyl group optionally substituted by 1 to 5 substituentsselected from halogen and optionally halogenated C₁₋₄ alkyl;R^(1b) is a hydrogen atom;R^(2b) is a C₁₋₈ alkyl group substituted by substituent(s) selected from(a) —O—(CH₂)_(n)—OH,(b) —O—(CH₂)_(n)—O—C₁₋₄ alkyl, and(c) —CO—NR⁸—(CH₂)_(n)—OH,wherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group;R^(3b) is a hydrogen atom or a C₁₋₆ alkyl group; andZ^(b) is a methylene group,[38] the compound of the above-mentioned [17], whereinR^(2c) is (i) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynylgroup, a C₁₋₈ alkyl-carbonyl group, a C₁₋₈ alkylsulfonyl group, a C₃₋₈cycloalkyl group, a C₆₋₁₈ aryl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl group, aC₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group, aC₆₋₁₈ aryl-sulfonyl group, a heterocyclic group, a heterocycle-C₁₋₄alkyl group, a heterocycle-carbonyl group or a heterocycle-C₁₋₄alkyl-carbonyl group, each of which is optionally substituted by 1 to 5substituents selected from the group (substituent group T) consisting of(a) halogen,(b) oxo,(c) optionally halogenated C₁₋₄ alkyl,(d) —(CH₂)_(m)-Q,(e) —(CH₂)_(m)-Z¹- (optionally halogenated C₁₋₄ alkyl),(f) —(CH₂)_(m)-Z¹-C₃— cycloalkyl,(g) —(CH₂)_(m)-Z²-(CH₂)_(n)-Q,(h) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹- (optionally halogenated C₁₋₄ alkyl),(i) —(CH₂)_(m)-Z²-(CH₂)_(m)-Z¹-C₃₋₈ cycloalkyl,(j) —(CH₂)_(m)-Z¹- (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom),(k) —(CH₂)_(m)-Z²-C₁₋₄ alkoxy, and(l) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹- (CH₂)_(n)-Z¹-C₁₋₄ alkylwherein m is an integer of 0 to 4, n is an integer of 1 to 4, Q ishydroxy, carboxy, cyano, nitro, —NR⁶R⁷, —CONR⁶R⁷ or SO₂NR⁶R⁷,Z¹ is —O—, —CO—, —C(OH)R⁸—, —C(═N—OR⁸)—, —S—, —SO—, —SO₂—, —N(COR⁸)—,—N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—, —NR⁸—CO₂—,—NR⁸—CO—NH—, —NR⁸—SO₂—, or —NR⁸—C(═NH)—NH—,Z² is —O—, —CO—, —C(OH)R⁸—, —C(═N—OR⁸)—, —S—, —SO—, —SO₂—, —NR⁸—,—N(COR⁸)—, —N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—,—NR⁸—CO₂—, —NR⁸—CO—NH—, —NR⁸—C(═NH)—NH—, —NR⁸—SO₂—, or —SO₂—NR⁸—,(CH₂)_(m) and (CH₂)_(n) are optionally substituted by 1 to 5substituents selected from halogen, optionally halogenated C₁₋₄ alkyland hydroxy, and when m or n is not less than 2, a subset —CH₂CH₂— of(CH₂)_(m) and (CH₂)_(n) is optionally replaced by —CH═CH—,R⁶ and R⁷ are the same or different and each is a hydrogen atom or aC₁₋₄ alkyl group, or R⁶ and R⁷ are bonded to form, together with anitrogen atom, a 3- to 8-membered saturated or unsaturated aliphaticheterocyclic group,R⁸ is a hydrogen atom or a C₁₋₄ alkyl group, and R⁹ is a C₁₋₄ alkylgroup, or(ii) a carbamoyl group optionally having 1 or 2 C₁₋₈ alkyl group(s)optionally substituted by substituent(s) selected from substituent groupT,wherein the carbamoyl group has two substituents, and they optionallyform, together with the adjacent nitrogen atom, a 3- to 8-memberedsaturated or unsaturated aliphatic heterocyclic group optionallysubstituted by substituent(s) selected from substituent group T,[39] the compound of the above-mentioned [17], wherein Bc is a benzenering optionally substituted by 1 to 4 substituents selected from halogenand optionally halogenated C₁₋₄ alkyl;C^(c) is a 5- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom(e.g., pyridyl, pyrimidinyl, 4-piperidyl), which is optionallysubstituted by 1 to 5 substituents selected from(i) halogen,(ii) C₁₋₄ alkyl,(iii) C₁₋₄ alkyl-carbonyl,(iv) optionally halogenated C₁₋₄ alkoxy-carbonyl,(v) C₃₋₈ cycloalkyl-carbonyl, and(vi) a carbamoyl group optionally substituted by substituent(s) selectedfrom(a) optionally halogenated C₁₋₈ alkyl,(b) C₃₋₈ cycloalkyl, and(c) C₆₋₁₈ aryl optionally substituted by substituent(s) selected fromhalogen, C₁₋₄ alkyl and C₁₋₄ alkyloxy;R^(1c) is (i) a hydrogen atom,(ii) a C₂₋₄ alkenyl group optionally substituted by hydroxy, or(iii) a 5- to 8-membered heterocyclic group having 1 to 3 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom;

R^(2c) is

(i) a C₁₋₄ alkyl group optionally substituted by substituent(s) selectedfrom(a) halogen,(b) hydroxy,(c) C₁₋₄ alkyloxy,(d) carboxy,(e) C₁₋₄ alkoxy-carbonyl,(f) —O—(CH₂)_(n)—OH,(g) —O—(CH₂)_(n)—O—C₁₋₄ alkyl,(h) —CO—NR⁸—(CH₂)_(n)—OH, and(i) —NR⁸—CO—(CH₂)_(n)—SO₂—C₁₋₁₄ alkylwherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group, or(ii) a C₆₋₁₈ aryl-C₁₋₄ alkyl group optionally substituted by C₁₋₄ alkyloptionally having hydroxy;R^(3c) is a hydrogen atom or a C₁₋₆ alkyl group; orR^(2c) and R^(3c) are optionally bonded to form C₂₋₄ alkylene,[40] the compound of the above-mentioned [17], whereinB^(c) is a benzene ring optionally substituted by 1 to 4 substituentsselected from halogen and C₁₋₄ alkyl;C^(c) is a 5- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,which is optionally substituted by 1 to 5 substituents selected from(i) C₁₋₄ alkyl,(ii) C₁₋₄ alkyl-carbonyl,(iii) optionally halogenated C₁₋₄ alkoxy-carbonyl,(iv) C₃₋₈ cycloalkyl-carbonyl, and(v) a carbamoyl group optionally substituted by substituent(s) selectedfrom(a) optionally halogenated C₁₋₈ alkyl,(b) C₃₋₈ cycloalkyl, and(c) C₆₋₁₈ aryl optionally substituted by halogen;R^(1c) is a hydrogen atom;R^(2c) is a C₁₋₄ alkyl group optionally substituted by substituent(s)selected from(a) hydroxy,(b) C₁₋₄ alkyloxy,(c) —O—(CH₂)_(n)—OH,(d) —O—(CH₂)_(n)—O—C₁₋₄ alkyl, and(e) —NR⁸—CO—(CH₂)_(n)—SO₂—C₁₋₄ alkylwherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group;R^(3c) is a hydrogen atom or a C₁₋₆ alkyl group,[41] the compound of the above-mentioned [40], whereinR^(2c) is a C₁₋₄ alkyl group optionally substituted by substituent(s)selected from(a) —O—(CH₂)_(n)—OH, and(b) —O—(CH₂)_(n)—O—C₁₋₄ alkyl, wherein n is an integer of 1 to 4,[42] the compound of the above-mentioned [18], whereinB^(d) is a benzene ring optionally substituted by halogen;C^(d) is a 5- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;R^(1d) is a hydrogen atom;

R^(2d) is

(i) C₁₋₄ alkyl optionally substituted by substituent(s) selected from(a) C₁₋₄ alkyloxy,(b) —O—(CH₂)_(n)—OH, and(c) —NR⁸—CO—(CH₂)_(n)—SO₂—C₁₋₄ alkylwherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group, or(ii) a 5- to 8-membered heterocycle-C₁₋₄ alkyl group having 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfuratom, which is optionally substituted by substituent(s) selected from(a) carboxy, and(b) C₁₋₄ alkoxy-carbonyl;R^(3d) is a hydrogen atom or a C₁₋₆ alkyl group; andZ^(d) is a C₁₋₃ alkylene group,[43] the compound of the above-mentioned [18], whereinB^(d) is a benzene ring optionally substituted by halogen;C^(d) is a 5- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;R^(1d) is a hydrogen atom;R^(2d) is a C₁₋₄ alkyl group optionally substituted by C₁₋₄ alkyloxy;R^(3d) is a hydrogen atom or a C₁₋₆ alkyl group; andZ^(d) is a methylene group,[44] the compound of the above-mentioned [19], whereinR^(2e) is (i) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynylgroup, a C₁₋₈ alkyl-carbonyl group, a C₁₋₈ alkylsulfonyl group, a C₃₋₈cycloalkyl group, a C₆₋₁₈ aryl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl group, aC₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group, aC₆₋₁₈ aryl-sulfonyl group, a heterocyclic group, a heterocycle-C₁₋₄alkyl group, a heterocycle-carbonyl group or a heterocycle-C₁₋₄alkyl-carbonyl group, each of which is optionally substituted by 1 to 5substituents selected from the group (substituent group T) consisting of(a) halogen,(b) oxo,(c) optionally halogenated C₁₋₄ alkyl,(d) —(CH₂)_(m)-Q,(e) —(CH₂)_(m)-Z¹- (optionally halogenated C₁₋₄ alkyl),(f) —(CH₂)_(m)-Z¹-C₃₋₈ cycloalkyl,(g) —(CH₂)_(m)-Z²- (CH₂)_(n)-Q,(h) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹- (optionally halogenated C₁₋₄ alkyl),(i) —(CH₂)_(m)-Z²- (CH₂)_(n)-Z¹-C₃₋₈ cycloalkyl,(j) —(CH₂)_(m)-Z¹- (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom),(k) —(CH₂)_(m)-Z²-C₁₋₄ alkoxy, and(l) —(CH₂)_(m)-Z²- (CH₂)_(n)-Z¹- (CH₂)_(m)-Z¹-C₁₋₄ alkylwherein m is an integer of 0 to 4, n is an integer of 1 to 4,Q is hydroxy, carboxy, cyano, nitro, —NR⁶R⁷, —CONR⁶R⁷ or —SO₂NR⁶R⁷,Z¹ is —O—, —CO—, —C(OH)R⁸—, —C(═N—OR⁸)—, —S—, —SO—, —SO₂—, —N(COR⁸)—,—N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—, —NR⁸—CO₂—,—NR⁸—CO—NH—, —NR⁸—SO₂—, or —NR⁸—C(═NH)—NH—,Z² is —O—, —CO—, —C(OH)R⁸—, —C(═N—OR⁸)—, —S—, —SO—, —SO₂—, —NR⁸—,—N(COR⁸)—, —N(CO₂R⁹)—, —N(SO₂R⁸)—, —CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—,—NR⁸—CO₂—, —NR⁸—CO—NH—, —NR⁸—C(═NH)—NH—, —NR⁸—SO₂—, or —SO₂—NR⁸—,(CH₂)_(m) and (CH₂)_(n) are optionally substituted by 1 to 5substituents selected from halogen, optionally halogenated C₁₋₄ alkyland hydroxy, and when m or n is not less than 2, a subset —CH₂CH₂— of(CH₂)_(m) and (CH₂)_(n) is optionally replaced by —CH═CH—,R⁶ and R⁷ are the same or different and each is a hydrogen atom or aC₁₋₄ alkyl group, or R⁶ and R⁷ are bonded to form, together with anitrogen atom, a 3- to 8-membered saturated or unsaturated aliphaticheterocyclic group,R⁸ is a hydrogen atom or a C₁₋₄ alkyl group, and R⁹ is a C₁₋₄ alkylgroup, or(ii) a carbamoyl group optionally having 1 or 2 C₁₋₈ alkyl group(s)optionally substituted by substituent(s) selected from substituent groupT,wherein the carbamoyl group has two substituents, and they optionallyform, together with the adjacent nitrogen atom, a 3- to 8-memberedsaturated or unsaturated aliphatic heterocyclic group optionallysubstituted by substituent(s) selected from substituent group T,[45] the compound of the above-mentioned [19], whereinB^(e) is a benzene ring optionally substituted by halogen;C^(e) is a phenyl group optionally substituted by optionally halogenatedC₁₋₄ alkyl;R^(2e) is a C₁₋₄ alkyl group optionally substituted by —O—(CH₂)_(n)—OHwherein n is an integer of 1 to 4,[46] the compound of the above-mentioned [19], whereinB^(e) is a benzene ring optionally substituted by halogen;C^(e) is a phenyl group optionally substituted by optionally halogenatedC₁₋₄ alkyl;R^(2e) is a C₁₋₄ alkyl group substituted by —O—(CH₂)_(n)—OH wherein n isan integer of 1 to 4,[47] the compound of the above-mentioned [20], whereinR^(2f) is (i) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynylgroup, a C₁₋₈ alkyl-carbonyl group, a C₁₋₈ alkylsulfonyl group, a C₃₋₈cycloalkyl group, a C₆₋₁₈ aryl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl group, aC₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group, aC₆₋₁₈ aryl-sulfonyl group, a heterocyclic group, a heterocycle-C₁₋₄alkyl group, a heterocycle-carbonyl group or a heterocycle-C₁₋₄alkyl-carbonyl group, each of which is optionally substituted by 1 to 5substituents selected from the group (substituent group T) consisting of(a) halogen,(b) oxo,(c) optionally halogenated C₁₋₄ alkyl,(d) —(CH₂)_(m)-Q,(e) —(CH₂)_(m)-Z¹- (optionally halogenated C₁₋₄ alkyl),(f) —(CH₂)_(m)-Z¹-C₃₋₈ cycloalkyl,(g) —(CH₂)_(m)-Z²-(CH₂)_(n)-Q,(h) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹- (optionally halogenated C₁₋₄ alkyl),(i) —(CH₂)_(m)-Z² (CH₂)_(n)-Z¹-C₃₋₈ cycloalkyl,(j) —(CH₂)_(m)-Z¹- (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom),(k) —(CH₂)_(m)-Z²-C₁₋₄ alkoxy, and(l) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹-(CH₂)_(n)-Z¹-C₁₋₄ alkylwherein m is an integer of 0 to 4, n is an integer of 1 to 4, Q ishydroxy, carboxy, cyano, nitro, —NR⁶R⁷, —CONR⁶R⁷ or —SO₂NR⁶R⁷,Z¹ is —O—, —CO—, —C(OH)R⁸—, —C(═N—OR⁸)—, —S—, —SO—, —SO₂—, —N(COR⁸)—,—N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—, —NR⁸—CO₂—,—NR⁸—CO—NH—, —NR⁸—SO₂—, or —NR⁸—C(═NH)—NH—,Z² is —O—, —CO—, —C(OH)R⁸—C(═N—OR⁸)—, —S—, —SO—, —SO₂—, —NR⁸—,—N(COR⁸)—, —N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—,—NR⁸—CO₂—, —NR⁸—CO—NH—, —NR⁸—C(═NH)—NH—, —NR⁸—SO₂—, or —SO₂—NR⁸—,(CH₂)_(m) and (CH₂)_(n) are optionally substituted by 1 to 5substituents selected from halogen, optionally halogenated C₁₋₄ alkyland hydroxy, and when m or n is not less than 2, a subset —CH₂CH₂— of(CH₂)_(m) and (CH₂)_(n) is optionally replaced by —CH═CH—,R⁶ and R⁷ are the same or different and each is a hydrogen atom or aC₁₋₄ alkyl group, or R⁶ and R⁷ are bonded to form, together with anitrogen atom, a 3- to 8-membered saturated or unsaturated aliphaticheterocyclic group,R⁸ is a hydrogen atom or a C₁₋₄ alkyl group, and R⁹ is a C₁₋₄ alkylgroup, or(ii) a carbamoyl group optionally having 1 or 2 C₁₋₈ alkyl group(s)optionally substituted by substituent(s) selected from substituent groupT,wherein the carbamoyl group has two substituents, and they optionallyform, together with the adjacent nitrogen atom, a 3- to 8-memberedsaturated or unsaturated aliphatic heterocyclic group optionallysubstituted by substituent(s) selected from substituent group T,[48] the compound of the above-mentioned [20], whereinB^(f) is a benzene ring optionally substituted by halogen;C^(f) is a phenyl group optionally substituted by halogen;

R^(2f) is

(i) a C₁₋₄ alkyl group optionally substituted by 1 to 5 substituentsselected from the group consisting of(a) hydroxy,(b) —O—(CH₂)_(n)—OH,(c) —NR⁸—(CH₂)_(n)—O—C₁₋₄ alkyl,(d) —NR⁸—(CH₂)_(n)-heterocyclic group (preferably, said heterocyclicgroup is a 5- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom),and(e) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,wherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group,(ii) a C₆₋₁₈ aryl group optionally substituted by 1 to 5 substituentsselected from the group consisting of(a) C₁₋₄ alkyl optionally substituted by substituent(s) selected fromhydroxy, —NR⁸—(CH₂)—OH, —NR⁸—(CH₂)_(n)—O—C₁₋₄ alkyl,—NR⁸—(CH₂)_(n)-heterocyclic group (preferably, said heterocyclic groupis a 5- to 8-membered heterocyclic group having 1 to 3 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom) and—NR⁸—(CH₂)—SO₂—C₁₋₄ alkyl, and(b) —CO—NR⁸—(CH₂)_(n)—O—C₁₋₄ alkyl,wherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group, or(iii) a C₆₋₁₈ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5substituents selected from the group consisting of(a) carboxy,(b) C₁₋₄ alkoxy-carbonyl, and(c) —CO—NR⁸—(CH₂)_(n)—O—C₁₋₄ alkyl, wherein n is an integer of 1 to 4,and R⁸ is a hydrogen atom or a C₁₋₄ alkyl group;R^(3f) is a hydrogen atom or a C₁₋₆ alkyl group; orR^(2f) and R^(3f) are optionally bonded to form C₂₋₄ alkylene; andZ^(f) is a C₁₋₃ alkylene group,[49] the compound of the above-mentioned [20], whereinB^(f) is a benzene ring optionally substituted by halogen;C^(f) is a phenyl group optionally substituted by halogen;R^(2f) is a C₁₋₄ alkyl group optionally substituted by 1 to 5substituents selected from the group consisting of (a) hydroxy, and(b) —O—(CH₂)_(n)—OH wherein n is an integer of 1 to 4;R^(3f) is a hydrogen atom or a C₁₋₆ alkyl group; andZ^(f) is methylene,[50] the compound of the above-mentioned [49], whereinR^(2f) is a C₁₋₄ alkyl group substituted by —O—(CH₂)_(n)—OH wherein n isan integer of 1 to 4,[51] the compound of the above-mentioned [21], whereinR^(2g) is (i) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynylgroup, a C₁₋₈ alkyl-carbonyl group, a C₁₋₈ alkylsulfonyl group, a C₃₋₈cycloalkyl group, a C₆₋₁₈ aryl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl group, aC₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group, aC₆₋₁₈ aryl-sulfonyl group, a heterocyclic group, a heterocycle-C₁₋₄alkyl group, a heterocycle-carbonyl group or a heterocycle-C₁₋₄alkyl-carbonyl group, each of which is optionally substituted by 1 to 5substituents selected from the group (substituent group T) consisting of(a) halogen,(b) oxo,(c) optionally halogenated C₁₋₄ alkyl,(d) —(CH₂)_(m)-Q,(e) —(CH₂)_(m)-Z¹- (optionally halogenated C₁₋₄ alkyl),(f) —(CH₂)_(m)-Z¹-C₃₋₈ cycloalkyl,(g) —(CH₂)_(m)-Z²-(CH₂)_(n)-Q,(h) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹- (optionally halogenated C₁₋₄ alkyl),(i) —(CH₂)_(m)-Z²-(CH₂)-Z¹-C₃₋₈ cycloalkyl,(j) —(CH₂)_(n)-Z¹- (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom),(k) —(CH₂)_(m)-Z²-C₁₋₄ alkoxy, and(l) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹-(CH₂)_(n)-Z¹-C₁₋₄ alkyl wherein m is aninteger of 0 to 4, n is an integer of 1 to 4,Q is hydroxy, carboxy, cyano, nitro, —NR⁶R⁷, —CONR⁶R⁷ or —SO₂NR⁶R⁷,Z¹ is —O—, —CO—, —C(OH)R⁸—, —C(═N—OR⁸)—, —S—, —SO—, —SO₂—, —N(COR⁸)—,—N(CO₂R⁹)—, —N(SO₂R⁸)—, —CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—, —NR⁸—CO₂—,—NR⁸—CO—NH—, —NR⁸—SO₂—, or —NR⁸—C(═NH)—NH—,Z² is —O—, —CO—, —C(OH)R⁸—, —C((═N—OR⁸)—, —S—, —SO—, —SO₂—, —NR⁸—,—N(COR⁸)—, —N(CO₂R⁹)—, —N(SO₂R⁸)—, —CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—,—NR⁸—CO₂—, —NR⁸—CO—NH—, —NR⁸—C(═NH)—NH—, —NR⁸—SO₂—, or —SO₂—NR⁸—,(CH₂)_(m) and (CH₂)_(n) are optionally substituted by 1 to 5substituents selected from halogen, optionally halogenated C₁₋₄ alkyland hydroxy, and when m or n is not less than 2, a subset —CH₂CH₂— of(CH₂), and (CH₂)_(n) is optionally replaced by —CH═CH—,R⁶ and R⁷ are the same or different and each is a hydrogen atom or aC₁₋₄ alkyl group, or R⁶ and R⁷ are bonded to form, together with anitrogen atom, a 3- to 8-membered saturated or unsaturated aliphaticheterocyclic group,R⁸ is a hydrogen atom or a C₁₋₄ alkyl group, and R⁹ is a C₁₋₄ alkylgroup, or(ii) a carbamoyl group optionally having 1 or 2 C₁₋₈ alkyl group(s)optionally substituted by substituent(s) selected from substituent groupT,wherein the carbamoyl group has two substituents, and they optionallyform, together with the adjacent nitrogen atom, a 3- to 8-memberedsaturated or unsaturated aliphatic heterocyclic group optionallysubstituted by substituent(s) selected from substituent group T,[52] the compound of the above-mentioned [21], whereinB^(g) is a benzene ring optionally substituted by C₁₋₄ alkyl;C^(g) is a 5- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,which is optionally substituted by C₁₋₄ alkyl

R^(2g) is

(i) a C₁₋₄ alkyl group optionally substituted by hydroxy,(ii) a C₆₋₁₈ aryl group optionally substituted by substituent(s)selected from (a) nitro,(b) amino,(c) —CO—NR⁸—(CH₂)_(n)—O—C₁₋₄ alkyl,(d) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,

(e) —NR⁸—CO—(CH₂)—NR⁶R⁷,

(f) —NR⁸—CO—(CH₂)_(n)—COOH(g) —NR⁸—CO—(CH₂)—CO₂—C₁₋₄ alkyl, and(h) —NR⁸—CO—(CH₂)_(m)—O—(CH₂)_(n)—O—C₁₋₄ alkyl, wherein m is an integerof 0 to 4, n is an integer of 1 to 4, R⁶ and R⁷ are the same ordifferent and each is a hydrogen atom or a C₁₋₄ alkyl group, and R⁸ is ahydrogen atom or a C₁₋₄ alkyl group, or(iii) a C₆₋₁₈ aryl-C₁₋₄ alkyl group optionally substituted bysubstituent(s) selected from(a) carboxy,(b) C₁₋₄ alkoxy-carbonyl, and(c) —CO—NR⁸—(CH₂)_(n)—O—C₁₋₄ alkyl,wherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group;R^(3g) is a hydrogen atom or a C₁₋₆ alkyl group; orR^(2g) and R^(3g) are optionally bonded to form C₂₋₄ alkylene,[53] the compound of the above-mentioned [21], wherein R^(2g) is(i) a C₆₋₁₈ aryl group optionally substituted by substituent(s) selectedfrom(a) nitro,(b) amino,(c) —CO—NR⁸—(CH₂)_(n)—O—C₁₋₄ alkyl,(d) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(e) —NR⁸—CO—(CH₂)_(n)—NR⁶R⁷,(f) —NR⁸—CO—(CH₂)_(n)—COOH(g) —NR⁸—CO—(CH₂)—CO₂—C₁₋₄ alkyl, and(h) —NR⁸—CO—(CH₂)_(m)—O—(CH₂)_(n)—O—C₁₋₄ alkyl,wherein m is an integer of 0 to 4, n is an integer of 1 to 4, R⁶ and R⁷are the same or different and each is a hydrogen atom or a C₁₋₄ alkylgroup, and R⁸ is a hydrogen atom or a C₁₋₄ alkyl group, or(ii) a C₆₋₁₈ aryl-C₁₋₄ alkyl group substituted by substituent(s)selected from(a) carboxy,(b) C₁₋₄ alkoxy-carbonyl, and(c) —CO—NR⁸—(CH₂)_(n)—O—C₁₋₄ alkyl,wherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group,[54] the compound of the above-mentioned [1], wherein A is a C₆₋₁₈ arylgroup substituted by substituent(s) selected from (i) a phenyloxy groupoptionally substituted by 1 to 5 substituents selected from(a) halogen,(b) optionally halogenated C₁₋₄ alkyl,(c) hydroxy-C₁₋₄ alkyl,(d) heterocycle-C₁₋₄ alkyl (preferably, 5- to 8-memberedheterocycle-C₁₋₄ alkyl, said 5- to 8-membered heterocycle has 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and anoptionally oxidized sulfur atom, such as imidazolyl, triazolyl and thelike),(e) optionally halogenated C₁₋₄ alkyloxy,(f) C₁₋₄ alkyl-carbonyl,(g) cyano,(h) carbamoyl optionally substituted by C₁₋₈ alkyl, and(i) C₁₋₄ alkoxy-carbonyl,(ii) a phenyl-C₁₋₃ alkyloxy group optionally substituted by 1 to 5substituents selected from(a) halogen,(b) optionally halogenated C₁₋₄ alkyl,(c) hydroxy-C₁₋₄ alkyl,(d) heterocycle-C₁₋₄ alkyl (preferably, 5- to 8-memberedheterocycle-C₁₋₄ alkyl, said 5- to 8-membered heterocycle has 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and anoptionally oxidized sulfur atom, such as imidazolyl, triazolyl and thelike),(e) optionally halogenated C₁₋₄ alkyloxy,(f) C₁₋₄ alkyl-carbonyl,(g) cyano,(h) carbamoyl optionally substituted by C₁₋₈ alkyl, and(i) C₁₋₄ alkoxy-carbonyl,(iii) a 5- to 8-membered heterocycleoxy group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,which is optionally substituted by 1 to 5 substituents selected from(a) halogen,(b) optionally halogenated C₁₋₄ alkyl,(c) hydroxy-C₁₋₄ alkyl,(d) heterocycle-C₁₋₄ alkyl (preferably, 5- to 8-memberedheterocycle-C₁₋₄ alkyl, said 5- to 8-membered heterocycle has 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and anoptionally oxidized sulfur atom, such as imidazolyl, triazolyl and thelike),(e) optionally halogenated C₁₋₄ alkyloxy,(f) C₁₋₄ alkyl-carbonyl,(g) cyano,(h) carbamoyl optionally substituted by C₁₋₈ alkyl, and(i) C₁₋₄ alkoxy-carbonyl, and(iv) 5- to 8-membered heterocycle-C₁₋₃ alkyloxy containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,which is optionally substituted by 1 to 5 substituents selected from (a)halogen,(b) optionally halogenated C₁₋₄ alkyl,(c) hydroxy-C₁₋₄ alkyl,(d) heterocycle-C₁₋₄ alkyl (preferably, 5- to 8-memberedheterocycle-C₁₋₄ alkyl, said 5- to 8-membered heterocycle has 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and anoptionally oxidized sulfur atom, such as imidazolyl, triazolyl and thelike),(e) optionally halogenated C₁₋₄ alkyloxy,(f) C₁₋₄ alkyl-carbonyl,(g) cyano,(h) carbamoyl optionally substituted by C₁₋₈ alkyl, and(i) C₁₋₄ alkoxy-carbonyl;wherein the C₆₋₁₈ aryl group is optionally further substituted by 1 to 4substituents selected from halogen, C₁₋₄ alkyl, hydroxy-C₁₋₄ alkyl andC₁₋₄ alkyloxy;

R¹ is

(i) a hydrogen atom,(ii) a cyano group, or(iii) a C₁₋₄ alkyl group or a C₂₋₄ alkenyl group, each of which isoptionally substituted by —NR⁸—CO—(CH₂)—NR⁶R⁷ wherein n is an integer of1 to 4, R⁶ and R⁷ are the same or different and each is a hydrogen atomor a C₁₋₄ alkyl group, R⁸ is a hydrogen atom or a C₁₋₄ alkyl group, andwhen n is not less than 2, a subset —CH₂CH₂— of (CH₂)_(n) is optionallyreplaced by —CH═CH—;

R² is

a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group or a C₂₋₈ alkynyl group, eachof which is optionally substituted by substituent(s) selected from(a) hydroxy,(b) carboxy,(c) cyano,(d) optionally halogenated C₁₋₄ alkyloxy,(e) —O—(CH₂)_(n)—OH,(f) —O—(CH₂)_(n)—O—CO—NH₂,(g) —O—(CH₂)_(n)—O— (optionally halogenated C₁₋₄ alkyl),(h) —O—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(i) —O—(CH₂)_(n)—SO₂—C₆₋₁₈ aryl,(j) —O—(CH₂)_(n)—SO₂—(CH₂)_(n)—OH,(k) —O—(CH₂)_(n)—NR⁸—CO—C₁₋₄ alkyl,(l) —O—(CH₂)_(n)—NR⁸—CO—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(m) —O—(CH₂)_(n)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(n) —CO—NR⁸—(CH₂)_(n)—OH,(o) —CO—NR⁸—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(p) —CO—NR⁸—O—C₁₋₄ alkyl,

(q) —NR⁶R⁷,

(r) —NR⁸—(CH₂)_(n)—OH,(s) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(t) —NR⁸—CO— (optionally halogenated C₁₋₄ alkyl),(u) —NR⁸—CO—(CH₂)_(n)—OH,(v) —NR⁸—CO—(CH₂)_(n)—CN,(w) —NR⁸—CO—(CH₂)_(n)—NR⁶R⁷,(x) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(y) —NR⁸—CO—(CH₂)_(n)—SO— (optionally halogenated C₁₋₄ alkyl),(z) —NR⁸—CO—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(aa) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(bb) —NR⁸—CO—(CH₂)_(n)—NR⁸—SO₂—C₁₋₄ alkyl,(cc) —NR⁸—CO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(dd) —NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(ee) —NR⁸—CO—NH—O—C₁₋₄ alkyl,(ff) —NR⁸—CO—NH—(CH₂)_(n)—O—C₁₋₄ alkyl,(gg) —NR⁸—C((═NH)—NH—C₁₋₄ alkyl,(hh) —NR⁸—SO₂—(CH₂)—SO₂—C₁₋₄ alkyl,

(ii) —S— (CH₂)—OH,

(jj) —SO—(CH₂)_(n)—OH,(kk) —SO₂—(CH₂)_(n)—OH, and(ll) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—O—C₁₋₄ alkyl,—CO—NH—C₁₋₄ alkyl, —CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂and the like) wherein n is an integer of 1 to 4, R⁶ and R⁷ are the sameor different and each is a hydrogen atom or a C₁₋₄ alkyl group, R⁸ is ahydrogen atom or a C₁₋₄ alkyl group, (CH₂)_(n) is optionally substitutedby halogenated C₁₋₄ alkyl or hydroxy, and when n is not less than 2, asubset —CH₂CH₂— of (CH₂)_(n) is optionally replaced by —CH═CH—;R³ is a hydrogen atom or a C₁₋₆ alkyl group; or,R¹ and R² are optionally bonded to form

R² and R³ are optionally bonded to form C₂₋₄ alkylene optionallysubstituted by an imino group.Particularly preferably, R² is a C₁₋₈ alkyl group, a C₂₋₈ alkenyl groupor a C₂₋₈ alkynyl group (particularly C₁₋₈ alkyl group), each of whichis optionally substituted by substituent(s) selected from(a) hydroxy,(b) carboxy,(c) cyano,(d) optionally halogenated C₁₋₄ alkyloxy,(e) —O—(CH₂)_(n)—OH (wherein (CH₂)_(n) is optionally substituted byhydroxy),(f) —O—(CH₂)_(n)—O—CO—NH₂,(g) —O—(CH₂)_(n)—O— (optionally halogenated C₁₋₄ alkyl),(h) —O—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(i) —O—(CH₂)—SO₂—C₆₋₁₈ aryl,

(j) —O—(CH₂)—SO₂—(CH₂)—OH,

(k) —O—(CH₂)_(n)—NR⁸—CO—C₁₋₄ alkyl,(l) —O—(CH₂)_(n)—NR⁸—CO—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(m) —O—(CH₂)_(n)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(n) —CO—NR⁸— (CH₂)_(n)—OH,(o) —CO—NR⁸— (CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(p) —CO—NR⁸—O—C₁₋₄ alkyl,

(q) —NR⁶R⁷,

(r) —NR⁸—(CH₂)_(n)—OH,(s) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(t) —NR⁸—CO— (optionally halogenated C₁₋₄ alkyl),(u) —NR⁸—CO—(CH₂)—OH (wherein (CH₂)_(n) is optionally substituted byoptionally halogenated C₁₋₄ alkyl or hydroxy),(v) —NR⁸—CO—(CH₂)_(n)—CN,(w) —NR⁸—CO—(CH₂)_(n)—NR⁶R⁷ (when n is not less than 2, a subset—CH₂CH₂— of (CH₂), is optionally replaced by —CH═CH—),(x) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(y) —NR⁸—CO—(CH₂)_(n)—SO— (optionally halogenated C₁₋₄ alkyl),(z) —NR⁸—CO—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(wherein (CH₂)_(n) is optionally substituted by C₁₋₄ alkyl),(aa) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(bb) —NR⁸—CO—(CH₂)_(n)—NR⁸—SO₂—C₁₋₄ alkyl,(cc) —NR⁸—CO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(dd) —NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(ee) —NR⁸—CO—NH—O—C₁₋₄ alkyl,(ff) —NR⁸—CO—NH—(CH₂)_(n)—O—C₁₋₄ alkyl,(gg) —NR⁸—C(═NH)—NH—C₁₋₄ alkyl,(hh) —NR⁸—SO₂—(CH₂)—SO₂—C₁₋₄ alkyl,(ii) —S—(CH₂)_(n)—OH,(jj) —SO—(CH₂)_(n)—OH,(kk) —SO₂—(CH₂)_(n)—OH, and(ll) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—O—C₁₋₄ alkyl,—CO—NH—C₁₋₄ alkyl, —CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂and the like), wherein n is an integer of 1 to 4, R⁶ and R⁷ are the sameor different and each is a hydrogen atom or a C₁₋₄ alkyl group, and R⁸is a hydrogen atom or a C₁₋₄ alkyl group,[55] the compound of the above-mentioned [1], whereinA is a C₆₋₁₈ aryl group substituted by substituent(s) selected from(i) a phenyloxy group substituted by 1 to 5 substituents selected from(a) halogen,(b) optionally halogenated C₁₋₄ alkyl,(c) hydroxy-C₁₋₄ alkyl,(d) heterocycle-C₁₋₄ alkyl (preferably, 5- to 8-memberedheterocycle-C₁₋₄ alkyl, said 5- to 8-membered heterocycle has 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and anoptionally oxidized sulfur atom, such as imidazolyl and the like),(e) optionally halogenated C₁₋₄ alkyloxy,(f) cyano,(g) carbamoyl optionally substituted by C₁₋₁₈ alkyl, and(h) C₁₋₄ alkoxy-carbonyl,(ii) a phenyl-C₁₋₃ alkyloxy group substituted by 1 to 5 substituentsselected from (a) halogen,(b) optionally halogenated C₁₋₄ alkyl,(c) hydroxy-C₁₋₄ alkyl,(d) heterocycle-C₁₋₄ alkyl (preferably, 5- to 8-memberedheterocycle-C₁₋₄ alkyl, said 5- to 8-membered heterocycle has 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and anoptionally oxidized sulfur atom, such as imidazolyl and the like),(e) optionally halogenated C₁₋₄ alkyloxy,(f) cyano,(g) carbamoyl optionally substituted by C₁₋₈ alkyl, and(h) C₁₋₄ alkoxy-carbonyl,(iii) a 5- to 8-membered heterocycleoxy group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,which is substituted by 1 to 5 substituents selected from(a) halogen,(b) optionally halogenated C₁₋₄ alkyl,(c) hydroxy-C₁₋₄ alkyl,(d) heterocycle-C₁₋₄ alkyl (preferably, 5- to 8-memberedheterocycle-C₁₋₄ alkyl, said 5- to 8-membered heterocycle has 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and anoptionally oxidized sulfur atom, such as imidazolyl and the like),(e) optionally halogenated C₁₋₄ alkyloxy,(f) cyano,(g) carbamoyl optionally substituted by C₁₋₈ alkyl, and(h) C₁₋₄ alkoxy-carbonyl, and(iv) 5- to 8-membered heterocycle-C₁₋₃ alkyloxy containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,which is substituted by 1 to 5 substituents selected from(a) halogen,(b) optionally halogenated C₁₋₄ alkyl,(c) hydroxy-C₁₋₄ alkyl,(d) heterocycle-C₁₋₄ alkyl (preferably, 5- to 8-memberedheterocycle-C₁₋₄ alkyl, said 5- to 8-membered heterocycle has 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and anoptionally oxidized sulfur atom, such as imidazolyl and the like),(e) optionally halogenated C₁₋₄ alkyloxy,(f) cyano,(g) carbamoyl optionally substituted by C₁₋₈ alkyl, and(h) C₁₋₄ alkoxy-carbonyl;wherein the C₆₋₁₈ aryl group is optionally further substituted by 1 to 4substituents selected from halogen and optionally halogenated C₁₋₄alkyl;R¹ is a hydrogen atom;R² is a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group or a C₂₋₈ alkynyl group,each of which is substituted by substituent(s) selected from(a) hydroxy,(b) optionally halogenated C₁₋₄ alkyloxy,(c) —O—(CH₂)_(n)—OH,(d) —O—(CH₂)_(n)—O—CO—NH₂,(e) —O—(CH₂)—O—C₁₋₄ alkyl,(f) —O—(CH₂)—SO₂— (optionally halogenated C₁₋₄ alkyl),(g) —O—(CH₂)—SO₂—C₆₋₁₈ aryl,(h) —O—(CH₂)_(n)—SO₂—(CH₂)_(n)—OH,(i) —O—(CH₂)_(n)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(j) —CO—NR⁸—(CH₂)_(n)—OH,(k) —CO—NR⁸—(CH₂)—SO₂— (optionally halogenated C₁₋₄ alkyl),

(l) —NR⁶R⁷,

(m) —NR⁸—(CH₂)_(n)—OH,(n) —NR⁸—(CH₂)—SO₂—C₁₋₄ alkyl,(o)—NR⁸—CO—(CH₂)_(n)—OH,(p) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(q) —NR⁸—CO—(CH₂)_(n)—SO— (optionally halogenated C₁₋₄ alkyl),(r) —NR⁸—CO—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(s) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(t) —NR⁸—CO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(u) —NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(v) —NR⁸—SO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(w) —S—(CH₂)_(n)—OH,(x) —SO—(CH₂)_(n)—OH,(y) —SO₂—(CH₂)_(n)—OH, and(z) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—NH—C₁₋₄ alkyl,—CONH₂—SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂ and the like),wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or differentand each is a hydrogen atom or a C₁₋₄ alkyl group, R⁸ is a hydrogen atomor a C₁₋₄ alkyl group, and (CH₂)_(n) is optionally substituted by C₁₋₄alkyl or hydroxy);R³ is a hydrogen atom or a C₁₋₆ alkyl group; or,R¹ and R² are optionally bonded to form

R² and R³ are optionally bonded to form C₂₋₄ alkylene, particularlypreferably, R² is a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group or a C₂₋₈alkynyl group (particularly, a C₁₋₈ alkyl group), each of which issubstituted by substituent(s) selected from (a) hydroxy,(b) optionally halogenated C₁₋₄ alkyloxy,(c) —O—(CH₂)_(n)—OH (wherein (CH₂)_(n) is optionally substituted byhydroxy),(d) —O—(CH₂)_(n)—O—CO—NH₂,(e) —O—(CH₂)_(n)—O—C₁₋₄ alkyl,(f) —O—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(g) —O—(CH₂)_(n)—SO₂—C₆₋₁₈ aryl,(h) —O—(CH₂)_(n)—SO₂—(CH₂)_(n)—OH,(i) —O—(CH₂)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(j) —CO—NR⁸—(CH₂)_(n)—OH,(k) —CO—NR⁸—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),

(l) —NR⁶R⁷,

(m) —NR⁸—(CH₂)_(n)—OH,(n) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(o) —NR⁸—CO—(CH₂)_(n)—OH (wherein (CH₂)_(n) is optionally substituted byC₁₋₄ alkyl),(p) —NR⁸—CO—(CH₂)—O—C₁₋₄ alkyl,(q) —NR⁸—CO—(CH₂)_(n)—SO— (optionally halogenated C₁₋₄ alkyl),(r) —NR⁸—CO—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(wherein (CH₂)_(n) is optionally substituted by C₁₋₄ alkyl),(s) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(t) —NR⁸—CO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(u) —NR⁸—CO—NH—(CH₂)—SO₂—C₁₋₄ alkyl,(v) —NR⁸—SO₂—(CH₂)—SO₂—C₁₋₄ alkyl,(w) —S— (CH₂)_(n)—OH,(x) —SO—(CH₂)_(n)—OH,

(y) —SO₂—(CH₂)—OH, and

(z) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—NH—C₁₋₄ alkyl,—CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂ and the like),wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or differentand each is a hydrogen atom or a C₁₋₄ alkyl group, and R⁸ is a hydrogenatom or a C₁₋₄ alkyl group,[56] the compound of the above-mentioned [55], whereinR² is (i) a C₅₋₈ alkyl group substituted by hydroxy,(ii) a C₁₋₈ alkyl group substituted by substituent(s) selected from(a) halogenated C₁₋₄ alkyloxy,

(b) —O—(CH₂)—OH,

(c) —O—(CH₂)_(n)—O—CO—NH₂,(d) —O—(CH₂)_(n)—O— (optionally halogenated C₁₋₄ alkyl),(e) —O—(CH₂)—SO₂— (optionally halogenated C₁₋₄ alkyl),(f) —O—(CH₂)_(n)—SO₂—C₆₋₁₈ aryl,(g) —O—(CH₂)_(n)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(h) —CO—NR⁸—(CH₂)_(n)—OH,(i) —CO—NR⁸—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(j) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(k) —NR⁸—CO—(CH₂)_(n)—OH,(l) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(m) —NR⁸—CO—(CH₂)_(n)—SO— (optionally halogenated C₁₋₄ alkyl),(n) —NR⁸—CO—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(o) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(p) —NR⁸—CO₂—(CH₂)—SO₂—C₁₋₄ alkyl,(q) —NR⁸—CO—NH—(CH₂)—SO₂—C₁₋₄ alkyl,(r) —NR⁸—SO₂—(CH₂)—SO₂—C₁₋₄ alkyl,

(s) —S—(CH₂)—OH, (t) —SO—(CH₂)—OH,

(u) —SO₂—(CH₂)_(n)—OH, and(v) —NR⁸CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—NH—C₁₋₄ alkyl,—CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂ and the like),wherein n is an integer of 1 to 4, R⁸ is a hydrogen atom or a C₁₋₄ alkylgroup, and (CH₂)_(n) is optionally substituted by C₁₋₄ alkyl,(iii) a C₂₋₈ alkenyl group optionally substituted by hydroxy, or(iv) a C₂₋₈ alkynyl group optionally substituted by hydroxy,particularly preferably, R² is(i) a C₅₋₈ alkyl group substituted by hydroxy,(ii) a C₁₋₈ alkyl group substituted by substituent(s) selected from(a) halogenated C₁₋₄ alkyloxy,(b) —O—(CH₂)_(n)—OH (wherein (CH₂)_(n) is optionally substituted byhydroxy),(c) —O—(CH₂)_(n)—O—CO—NH₂,(d) —O—(CH₂)—O— (optionally halogenated C₁₋₄ alkyl),(e) —O—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(f) —O—(CH₂)_(n)—SO₂—C₆₁₈ aryl,(g) —O—(CH₂)_(n)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(h) —CO—NR⁸—(CH₂)_(n)—OH,(i) —CO—NR⁸—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(j) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(k) —NR⁸—CO—(CH₂)_(n)—OH (wherein (CH₂)_(n) is optionally substituted byC₁₋₄ alkyl),(l) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(m) —NR⁸CO—(CH₂)_(n)—SO— (optionally halogenated C₁₋₄ alkyl),(n) —NR⁸—CO(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(wherein (CH₂), is optionally substituted by C₁₋₄ alkyl),(o) —NR⁸—CO(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(p) —NR⁸—CO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(q) —NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(r) —NR⁸—SO₂—(CH₂)—SO₂—C₁₋₄ alkyl,(s) —S—(CH₂)_(n)—OH,(t) —SO—(CH₂)_(n)—OH,(u) —SO₂—(CH₂)_(n)—OH, and(v) —NR⁸CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—NH—C₁₋₄ alkyl,—CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂ and the like),wherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group,(iii) a C₂₋₈ alkenyl group optionally substituted by hydroxy, or(iv) a C₂₋₈ alkynyl group optionally substituted by hydroxy,[57] the compound of the above-mentioned [1], which is selected from thefollowing (A) to (H):(A) a compound (I) wherein

W is CR¹;

A is a phenyloxy-C₆₋₁₈ aryl group wherein the phenyloxy moiety isoptionally substituted by 1 to 5 substituents selected from(i) halogen,(ii) optionally halogenated C₁₋₄ alkyl,(iii) hydroxy-C₁₋₄ alkyl,(iv) heterocycle-C₁₋₄ alkyl (preferably, 5- to 8-memberedheterocycle-C₁₋₄ alkyl, said 5- to 8-membered heterocycle has 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and anoptionally oxidized sulfur atom, such as imidazolyl, triazolyl and thelike),(v) optionally halogenated C₁₋₄ alkyloxy,(vi) C₁₋₄ alkyl-carbonyl,(vii) cyano,(viii) carbamoyl optionally substituted by C₁₋₈ alkyl, and(ix) C₁₋₄ alkoxy-carbonyl, and the C₆₋₁₈ aryl moiety is optionallyfurther substituted by 1 to 4 substituents selected from halogen, C₁₋₄alkyl, hydroxy-C₁₋₄ alkyl, C₁₋₄ alkyloxy, carboxy and C₁₋₄alkoxy-carbonyl;X¹ is —NR^(3′)— wherein R^(3′) is a hydrogen atom or a C₁₋₆ alkyl group;

R¹ is

(i) a hydrogen atom,(ii) a cyano group, or(iii) a C₁₋₄ alkyl group or a C₂₋₄ alkenyl group, each of which isoptionally substituted by —NR⁸—CO—(CH₂)_(n)—NR⁶R⁷ wherein n is aninteger of 1 to 4, R⁶ and R⁷ are the same or different and each is ahydrogen atom or a C₁₋₄ alkyl group, R⁸ is a hydrogen atom or a C₁₋₄alkyl group, and when n is not less than 2, a subset —CH₂CH₂— of(CH₂)_(n) is optionally replaced by —CH═CH—; andR² is (i) a hydrogen atom or(ii) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group or a C₂₋₈ alkynyl group,each of which is optionally substituted by substituent(s) selected from(a) hydroxy,(b) carboxy,(c) cyano,(d) optionally halogenated C₁₋₄ alkyloxy,(e) —O—(CH₂)_(n)—OH,(f) —O—(CH₂)_(n)—O—CO—NH₂,(g) —O—(CH₂)_(n)—O— (optionally halogenated C₁₋₄ alkyl),(h) —O—(CH₂)—SO₂— (optionally halogenated C₁₋₄ alkyl),(i) —O—(CH₂)—SO₂—C₆₋₁₈ aryl,(j) —O—(CH₂)_(n)—SO₂—(CH₂)_(n)—OH,(k) —O—(CH₂)_(n)—NR⁸—CO—C₁₋₄ alkyl,(l) —O—(CH₂)—NR⁸—CO—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(m) —O—(CH₂)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(n) —CO—NR⁸ (CH₂)_(n)—OH,(o) —CO—NR⁸—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(p) —CO—NR⁸—O—C₁₋₄ alkyl,

(q) —NR⁶R⁷,

(r) —NR⁸—(CH₂)_(n)—OH,(s) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(t) —NR⁸—CO— (optionally halogenated C₁₋₄ alkyl),(u) —NR⁸—CO—(CH₂)_(n)—OH,(v) —NR⁸—CO—(CH₂)_(n)—CN,(w) —NR⁸—CO—(CH₂)_(n)—NR⁶R⁷,(x) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(y) —NR⁸—CO—(CH₂)_(n)—SO— (optionally halogenated C₁₋₄ alkyl)(z) —NR⁸—CO—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(aa) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(bb) —NR⁸—CO—(CH₂)_(n)—NR⁸—SO₂—C₁₋₄ alkyl,(cc) —NR⁸—CO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(dd) —NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(ee) —NR⁸—CO—NH—O—C₁₋₄ alkyl,(ff) —NR⁸—CO—NH—(CH₂)_(n)—O—C₁₋₄ alkyl,(gg) —NR⁸—C(═NH)—NH—C₁₋₄ alkyl,(hh) —NR⁸—SO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(ii) —S— (CH₂)_(n)—OH,(jj) —SO—(CH₂)_(n)—OH,(kk) —SO₂—(CH₂)_(n)—OH, and(ll) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—O—C₁₋₄ alkyl,—CO—NH—C₁₋₄ alkyl, —CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂and the like), wherein n is an integer of 1 to 4, R⁶ and R⁷ are the sameor different and each is a hydrogen atom or a C₁₋₄ alkyl group, R⁸ is ahydrogen atom or a C₁₋₄ alkyl group, (CH₂)_(n) is optionally substitutedby optionally halogenated C₁₋₄ alkyl or hydroxy, and when n is not lessthan 2, a subset —CH₂CH₂— of (CH₂), is optionally replaced by —CH═CH—;orR¹ and R² are optionally bonded to form

R² and R^(3′) are optionally bonded to form C₂₋₄ alkylene optionallysubstituted by an imino group, particularly preferably, R^(2a) is a C₁—alkyl group, a C₂₋₈ alkenyl group or a C₂₋₈ alkynyl group (particularly,C₁₋₈ alkyl group), each of which is optionally substituted bysubstituent(s) selected from(a) hydroxy,(b) carboxy,(c) cyano,(d) optionally halogenated C₁₋₄ alkyloxy,(e) —O—(CH₂)_(n)—OH (wherein (CH₂), is optionally substituted byhydroxy),(f) —O—(CH₂)_(n)—O—CO—NH₂,(g) —O—(CH₂)_(n)—O— (optionally halogenated C₁₋₄ alkyl),(h) —O—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(i) —O—(CH₂)—SO₂—C₆₋₁₈ aryl,(j) —O—(CH₂)_(n)—SO₂—(CH₂)_(n)—OH,(k) —O—(CH₂)—NR⁸—CO—C₁₋₄ alkyl,(l) —O—(CH₂)_(n)—NR⁸—CO—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(m) —O—(CH₂)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(n) —CO—NR⁸—(CH₂)_(n)—OH,(o) —CO—NR⁸—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl), (p)—CO—NR⁸—O—C₁₋₄ alkyl,

(q) —NR⁶R⁷, (r) —NR⁸—(CH₂)—OH,

(s) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(t) —NR⁸—CO— (optionally halogenated C₁₋₄ alkyl),(u) —NR⁸—CO—(CH₂)_(n)—OH (wherein (CH₂)_(n) is optionally substituted byoptionally halogenated C₁₋₄ alkyl or hydroxy),(v) —NR⁸—CO—(CH₂)_(n)—CN,(w) —NR⁸—CO—(CH₂)—NR⁶R⁷ (when n is not less than 2, a subset —CH₂CH₂— of(CH₂)_(n) is optionally replaced by —CH═CH—),(x) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(y) —NR⁸—CO—(CH₂)—SO— (optionally halogenated C₁₋₄ alkyl),(z) —NR⁸—CO—(CH₂)—SO₂— (optionally halogenated C₁₋₄ alkyl)(wherein (CH₂)_(n) is optionally substituted by C₁₋₄ alkyl),(aa) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(bb) —NR⁸—CO—(CH₂)_(n)—NR⁸—SO₂—C₁₋₄ alkyl,(cc) —NR⁸—CO₂—(CH₂)—SO₂—C₁₋₄ alkyl,(dd) —NR⁸—CO—NH—(CH₂)—SO₂—C₁₋₄ alkyl,(ee) —NR⁸—CO—NH—O—C₁₋₄ alkyl,(ff) —NR⁸—CO—NH—(CH₂)—O—C₁₋₄ alkyl,(gg) —NR⁸—C(═NH)—NH—C₁₋₄ alkyl,(hh) —NR⁸—SO₂—(CH₂)—SO₂—C₁₋₄ alkyl,

(ii) —S—(CH₂)—OH,

(jj) —SO—(CH₂)_(n)—OH,(kk) —SO₂—(CH₂)_(n)—OH, and(ll) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—O—C₁₋₄ alkyl,—CO—NH—C₁₋₄ alkyl, —CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂and the like), wherein n is an integer of 1 to 4, R⁶ and R⁷ are the sameor different and each is a hydrogen atom or a C₁₋₄ alkyl group, and R⁸is a hydrogen atom or a C₁₋₄ alkyl group,(B) a compound (I) wherein

W is CR¹;

A is phenyl-C₁₋₃ alkyloxy-C₆₋₁₈ aryl group wherein the phenyl moiety isoptionally substituted by 1 to 5 substituents selected from halogen,optionally halogenated C₁₋₄ alkyl and cyano, andthe C₆₋₁₈ aryl moiety is optionally further substituted by 1 to 4substituents selected from halogen, C₁₋₄ alkyl optionally having hydroxyand C₁₋₄ alkyloxy;X¹ is —NR^(3′)— wherein R^(3′) is a hydrogen atom or a C₁₋₆ alkyl group;R¹ is (i) a hydrogen atom,(ii) a C₁₋₄ alkyl group or a C₂₋₄ alkenyl group, each of which isoptionally substituted by substituent(s) selected from(a) hydroxy,(b) amino,(c) —NR⁸—CO—(CH₂)_(n)—NR⁶R⁷, and(d) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl wherein n is an integer of 1 to 4, R⁶and R⁷ are the same or different and each is a hydrogen atom or a C₁₋₄alkyl group, R⁸ is a hydrogen atom or a C₁₋₄ alkyl group, and when n isnot less than 2, a subset —CH₂—CH₂ of (CH₂)_(n) is optionally replacedby —CH═CH—, or(iii) a C₆₋₁₈ aryl group optionally substituted by substituent(s)selected from(a) amino,(b) carboxy, and(c) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkylwherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group, or(iv) a 5- to 8-membered heterocyclic group having 1 to 3 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom; andR² is (i) a hydrogen atom,(ii) a C₁₋₈ alkyl group optionally substituted by substituent(s)selected from(a) halogen,(b) hydroxy,(c) C₁₋₄ alkyloxy,

(d) —O—(CH₂)—OH,

(e) —O—(CH₂)_(n)—O—C₁₋₄ alkyl,(f) —CO—NR⁸—(CH₂)_(n)—OH,

(g) —NR⁶R⁷, and

(h) —NR⁸—(CH₂)_(n)—OHwherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or differentand each is a hydrogen atom or a C₁₋₄ alkyl group, and R⁸ is a hydrogenatom or a C₁₋₄ alkyl group,(iii) a C₆₋₁₈ aryl-C₁₋₄ alkyl group optionally substituted bysubstituent(s) selected from (a) C₁₋₄ alkyl optionally having hydroxy,(b) carboxy,(c) C₁₋₄ alkoxy-carbonyl,(d) 5- to 8-membered heterocycle-carbonyl having 1 to 3 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom, whichoptionally has substituent(s) selected from hydroxy and C₁₋₄ alkyl, and(e) C₁₋₄ alkyl-carbamoyl optionally having substituent(s) selected fromhydroxy and carbamoyl,(iv) a C₆₋₁₈ aryl-carbonyl group optionally substituted by C₁₄ alkoxy,(v) a C₆₋₁₈ aryl-sulfonyl group optionally substituted by C₁₋₄ alkoxy,or(vi) a 5- to 8-membered heterocycle-C₁₋₄ alkyl group having 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfuratom, which is optionally substituted by substituent(s) selected from(a) carboxy, and(b) C₁₋₄ alkoxy-carbonyl; orR² and R^(3′) are optionally bonded to form C₂₋₄ alkylene,(C) a compound (I) wherein W is CR¹;A is a 5- to 8-membered heterocycleoxy-C₆₋₁₈ aryl group containing 1 to3 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom, wherein the heterocycleoxy moiety is optionally substitutedby 1 to 5 substituents selected from(i) halogen,(ii) C₁₋₄ alkyl,(iii) C₁₋₄ alkyl-carbonyl,(iv) optionally halogenated C₁₋₄ alkoxy-carbonyl,(v) C₃₋₈ cycloalkyl-carbonyl, and(vi) a carbamoyl group optionally substituted by substituent(s) selectedfrom(a) optionally halogenated C₁₋₁₈ alkyl,(b) C₃₋₈ cycloalkyl, and(c) C₆₋₁₈ aryl optionally substituted by substituent(s) selected fromhalogen, C₁₋₄ alkyl and C₁₋₄ alkyloxy, and the C₆₋₁₈ aryl moiety isoptionally further substituted by 1 to 4 substituents selected fromhalogen and optionally halogenated C₁₋₄ alkyl;X¹ is —NR^(3′)— wherein R^(3′) is a hydrogen atom or a C₁₋₆ alkyl group;R¹ is (i) a hydrogen atom,(ii) a C₁₋₄ alkyl group or a C₂₋₄ alkenyl group, each of which isoptionally substituted by substituent(s) selected from(a) hydroxy,(b) amino,(c) —NR⁸—CO—(CH₂)_(n)—NR⁶R⁷, and(d) —NR—CO—(CH₂)_(n)—O—C₁₋₄ alkyl, wherein n is an integer of 1 to 4, R⁶and R⁷ are the same or different and each is a hydrogen atom or a C₁₋₄alkyl group, R⁸ is a hydrogen atom or a C₁₋₄ alkyl group, and when n isnot less than 2, a subset —CH₂CH₂— of (CH₂), is optionally replaced by—CH═CH—,(iii) a C₆₋₁₈ aryl group optionally substituted by substituent(s)selected from(a) C₁₋₄ alkyl optionally substituted by substituent(s) selected fromhydroxy, —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl and —NR⁸—CO—(CH₂)—O—C₁₋₄ alkyl,(b) amino,(c) C₁₋₄ alkyloxy,(d) carboxy, and(e) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,wherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group, or(iv) a 5- to 8-membered heterocyclic group having 1 to 3 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom; andR² is (i) a hydrogen atom,(ii) a C₁₋₄ alkyl group optionally substituted by substituent(s)selected from(a) halogen,(b) hydroxy,(c) C₁₋₄ alkyloxy,(d) carboxy,(e) C₁₋₄ alkoxy-carbonyl,(f) —O—(CH₂)_(n)—OH,(g) —O—(CH₂)_(n)—O—C₁₋₄ alkyl,

(h) —CO—NR⁸—(CH₂)—OH, and

(i) —NR⁸—CO—(CH₂)—SO₂—C₁₋₄ alkylwherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group, or(iii) a C₆₋₁₈ aryl-C₁₋₄ alkyl group optionally substituted by C₁₋₄ alkyloptionally having hydroxy; orR² and R^(3′) are optionally bonded to form C₂₋₄ alkylene,(D) a compound (I) wherein

W is CR¹;

A is 5- to 8-membered heterocycle-C₁₋₃ alkyloxy-C₆₋₁₈ aryl groupcontaining 1 to 3 hetero atoms selected from a nitrogen atom, an oxygenatom and a sulfur atomwherein the C₆₋₁₈ aryl moiety is optionally further substituted byhalogen;X¹ is —NR^(3′) wherein R^(3′) is a hydrogen atom or a C₁₋₆ alkyl group;R¹ is (i) a hydrogen atom or(ii) a 5- to 8-membered heterocyclic group having 1 to 3 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom; andR² is (i) a hydrogen atom,(ii) C₁₋₄ alkyl optionally substituted by substituent(s) selected from(a) C₁₋₄ alkyloxy,(b) —O—(CH₂)_(n)—OH, and(c) —NR⁸—CO—(CH₂)_(n)—SO₂—C₁₋₄ alkylwherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group, or(iii) a 5- to 8-membered heterocycle-C₁₋₄ alkyl group having 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfuratom, which is optionally substituted by substituent(s) selected from(a) carboxy, and(b) C₁₋₄ alkoxy-carbonyl,(E) a compound (I) wherein

W is N;

A is a phenyloxy-C₆₋₁₈ aryl group wherein the phenyloxy moiety isoptionally substituted by 1 to 5 substituents selected from optionallyhalogenated C₁₋₄ alkyl and cyano, and the C₆₋₁₈ aryl moiety isoptionally further substituted by 1 to 4 substituents selected fromhalogen and C₁₋₄ alkyl;X¹ is —NR^(3′)— wherein R³ is a hydrogen atom or a C₁₋₆ alkyl group; andR² is (i) a hydrogen atom or(ii) a C₁₋₄ alkyl group optionally substituted by —O—(CH₂)_(n)—OHwherein n is an integer of 1 to 4,(F) a compound (I) wherein

W is N;

A is a phenyl-C₁₋₃ alkyloxy-C₆₋₁₈ aryl group wherein the phenyl moietyis optionally substituted by 1 to 5 substituents selected from halogenand cyano, and the C₆₋₁₈ aryl moiety is optionally further substitutedby 1 to 4 substituents selected from halogen and C₁₋₄ alkyl;X¹ is —NR³— wherein R³ is a hydrogen atom or a C₁₋₆ alkyl group; andR² is (i) a hydrogen atom,(ii) a C₁₋₄ alkyl group optionally substituted by 1 to 5 substituentsselected from the group consisting of(a) hydroxy,(b) —O—(CH₂)_(n)—OH,(c) —NR⁸—(CH₂)_(n)—O—C₁₋₄ alkyl,(d) —NR⁸—(CH₂)_(n)-heterocyclic group (preferably, said heterocyclicgroup is a 5- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom),and(e) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl wherein n is an integer of 1 to 4, andR⁸ is a hydrogen atom or a C₁₋₄ alkyl group,(iii) a C₆₋₁₈ aryl group optionally substituted by C₁₋₄ alkyl optionallysubstituted by substituent(s) selected from hydroxy, —NR⁸—(CH₂)—OH,—NR⁸—(CH₂)_(n)-heterocyclic group (preferably, said heterocyclic groupis a 5- to 8-membered heterocyclic group having 1 to 3 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom) and—NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl, or(iv) a C₆₋₁₈ aryl-C₁₋₁₄ alkyl group optionally substituted by 1 to 5substituents selected from the group consisting of(a) carboxy,(b) C₁₋₄ alkoxy-carbonyl, and(c) —CO—NR⁸—(CH₂)_(n)—O—C₁₋₁₄ alkylwherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group; orR² and R^(3′) are optionally bonded to form C₂₋₄ alkylene,(G) a compound (I) wherein

W is N;

A is a 5- to 8-membered heterocycleoxy-C₆₋₁₈ aryl group containing 1 to3 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom wherein the heterocycleoxy moiety is optionally substitutedby C₁₋₄ alkyl, and the C₆₋₁₈ aryl moiety is optionally furthersubstituted by C₁₋₄ alkyl;X¹ is —NR^(3′)— wherein R^(3′) is a hydrogen atom or a C₁₋₆ alkyl group;andR² is (i) a hydrogen atom,(ii) a C₁₋₄ alkyl group optionally substituted by hydroxy,(iii) a C₆₋₁₈ aryl group optionally substituted by substituent(s)selected from(a) nitro,(b) amino,(c) —CO—NR⁸—(CH₂)_(n)—O—C₁₋₄ alkyl,(d) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(e) —NR⁸—CO—(CH₂)_(n)—NR⁶R⁷,(f) —NR⁸—CO—(CH₂)_(n)—COOH(g) —NR⁸—CO—(CH₂)_(n)—CO₂—C₁₋₄ alkyl, and(h) —NR⁸—CO—(CH₂)-mO (CH₂)_(n)—O—C₁₋₄ alkylwherein m is an integer of 0 to 4, n is an integer of 1 to 4, R⁶ and R⁷are the same or different and each is a hydrogen atom or a C₁₋₄ alkylgroup, and R⁸ is a hydrogen atom or a C₁₋₄ alkyl group, or(iv) a C₆₋₁₈ aryl-C₁₋₄ alkyl group optionally substituted bysubstituent(s) selected from (a) carboxy,(b) C₁₋₄ alkoxy-carbonyl,(c) —CO—NR⁸—(CH₂)_(n)—O—C₁₋₄ alkyl, wherein n is an integer of 1 to 4,and R⁸ is a hydrogen atom or a C₁₋₄ alkyl group); orR² and R^(3′) are optionally bonded to form C₂₋₄ alkylene,(H) a compound (I) wherein

W is CH;

A is a C₆₋₁₈ aryl group optionally substituted by substituent(s)selected from(a) carboxy,(b) C₁₋₄ alkoxy-carbonyl,(c) a 5- to 8-membered heterocycle-carbonyl group containing 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfuratom (preferably, a 5- to 8-membered cyclic amino-carbonyl groupoptionally having 1 or 2 hetero atoms selected from a nitrogen atom, anoxygen atom and a sulfur atom), which is optionally substituted by C₆₋₁₈aryl-C₁₋₄ alkyl;(d) a carbamoyl group optionally substituted by C₆₋₁₈ aryl-C₁₋₄ alkyl,and(e) a ureido group optionally substituted by C₆₋₁₈ aryl-C₁₋₄ alkyl;X¹ is —NR^(3′)— wherein R^(3′) is a hydrogen atom or a C₁₋₆ alkyl group;and R² is a hydrogen atom,[58] the compound of the above-mentioned [1], wherein A is (i) a C₆₋₁₈aryl group or (ii) a 5- to 8-membered heteroaryl group containing, as anatom (ring atom) constituting a ring system, 1 to 4 hetero atomsselected from an oxygen atom, an optionally oxidized sulfur atom and anitrogen atom (preferably, an oxygen atom, a sulfur atom and a nitrogenatom), each of which is optionally substituted by 1 to 5 substituentsselected from halogen, optionally halogenated C₁₋₄ alkyl, hydroxy,optionally halogenated C₁₋₄ alkyloxy, C₁₋₄ alkyloxymethyl, hydroxy-C₁₋₄alkyl, C₁₋₄ alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano,carbamoyl, sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino, C₁₋₄ alkylsulfonylamino and a group of the formula—Y²—B,wherein Y² is a single bond, —O—, —O—(C₁₋₃ alkylene)-, —NH— or —S—,

B is

(A) (i) a C₆₋₁₈ aryl group, (ii) a 5- to 8-membered heteroaryl groupcontaining, as an atom (ring atom) constituting a ring system, 1 to 4hetero atoms selected from an oxygen atom, an optionally oxidized sulfuratom and a nitrogen atom (preferably, an oxygen atom, a sulfur atom anda nitrogen atom) or a saturated or unsaturated aliphatic heterocyclicgroup, (iii) a C₃₋₈ cycloalkyl group, (iv) a carbamoyl group,(v) a C₆₋₁₈ aryl-carbonyl group or (vi) a C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonylgroup, each of which is optionally substituted by 1 to 5 substituentsselected from halogen, optionally halogenated C₁₋₄ alkyl, hydroxy,optionally halogenated C₁₋₄ alkyloxy, C₁₋₄ alkyloxymethyl, hydroxy-C₁₋₄alkyl, C₁₋₄ alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano,carbamoyl, sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino or (B) a ureido groupoptionally having 1 or 2 C₁₋₈ alkyl group(s) optionally substituted bysubstituent(s) selected from substituent group T,wherein the ureido group has two substituents, and they optionally form,together with the adjacent nitrogen atom, a 3- to 8-membered saturatedor unsaturated aliphatic heterocyclic group optionally substituted bysubstituent(s) selected from substituent group T,wherein the substituent group T is a group consisting of(a) halogen,(b) oxo,(c) optionally halogenated C₁₋₄ alkyl,(d) —(CH₂)_(m)-Q,(e) —(CH₂)_(m)-Z¹- (optionally halogenated C₁₋₄ alkyl),(f) —(CH₂)_(m)-Z¹-C₃₋₈ cycloalkyl,(g) —(CH₂)_(m)-Z² (CH₂)_(n)-Q,(h) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹- (optionally halogenated C₁₋₄ alkyl),(i) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹-C₃₋₈ cycloalkyl,(j) —(CH₂)_(m)-Z¹- (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom),(k) —(CH₂)_(m)-Z²-C₁₋₄ alkoxy, and(l) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹-(CH₂)_(n)-Z¹-C₁₋₄ alkylwherein m is an integer of 0 to 4, n is an integer of 1 to 4, Q ishydroxy, carboxy, cyano, nitro, —NR⁶R⁷, —CONR⁶R⁷, —OCONH₂ or —SO₂NR⁶R⁷,Z¹ is —O—, —CO—, —C(OH)R⁸—, —C(═N—OR⁸)—, —S—, —SO—, —SO₂—, —N(COR⁸)—,—N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—, —NR⁸—CO₂—,—NR⁸—CO—NH—, —NR⁸—SO₂—, or —NR⁸—C(═NH)—NH—,Z² is —O—, —CO—, —C(OH)R⁸—, —C(═N—OR⁸)—, —S—, —SO—, —SO₂—,—NR⁸—N(COR⁸)—, —N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁸—,—NR⁸—CO—, —NR⁸—CO₂—, —NR⁸—CO—NH—, —NR⁸—C(═NH)—NH—, —NR⁸—SO₂—, or—SO₂—NR⁸—,(CH₂)_(m) and (CH₂)_(n) are optionally substituted by 1 to 5substituents selected from halogen, optionally halogenated C₁₋₄ alkyland hydroxy, and when m or n is not less than 2, a subset —CH₂CH₂— of(CH₂)_(m) and (CH₂)_(n) is optionally replaced by —CH═CH— or —C≡C—,R⁶ and R⁷ are the same or different and each is a hydrogen atom or aC₁₋₄ alkyl group, or R⁶ and R⁷ form, together with a nitrogen atom, a 3-to 8-membered saturated or unsaturated aliphatic heterocyclic groupoptionally substituted by 1 to 5 substituents selected from halogen,optionally halogenated C₁₋₄ alkyl, hydroxy, optionally halogenated C₁₋₄alkyloxy, C₁₋₄ alkyloxymethyl, hydroxy C₁₋₄ alkyl, C₁₋₄ alkyl-carbonyl,carboxy, C₁₋₄ alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro,amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄ alkoxy-carbonylamino and C₁₋₄alkylsulfonylamino,R⁸ is a hydrogen atom or C₁₋₄ alkyl, and R⁹ is C₁₋₄ alkyl, R³ is (i) ahydrogen atom, or(ii) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynyl group or aC₃₋₈ cycloalkyl group, each of which is optionally substituted by 1 to 3substituents selected from halogen, hydroxy, C₁₋₄ alkyloxy, C₁₋₄alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano, carbamoyl,sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino, orR³ is optionally bonded to a carbon atom or a hetero atom on the arylgroup or the heteroaryl group represented by A to form a saturated orunsaturated 4- to 8-membered nitrogen-containing heterocycle, which isoptionally substituted by 1 to 3 substituents selected from halogen,hydroxy, C₁₋₄ alkyloxy, C₁₋₄ alkyl-carbonyl, carboxy, C₁₋₄alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C₁₋₄alkyl-carbonylamino, C₁₋₄ alkoxy-carbonylamino and C₁₋₄alkylsulfonylamino,Y¹ is (i) a single bond or(ii) C₁₋₄ alkylene or —O—(C₁₋₄ alkylene)-, each of which is optionallysubstituted by 1 to 3 substituents selected from halogen, hydroxy, C₁₋₄alkyloxy, C₁₋₄ alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano,carbamoyl, sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino,R¹ is (i) a hydrogen atom or(ii) a group represented by the formula —X²—R⁴,wherein X² is a single bond, —NH— or —O—, andR⁴ is (i) a hydrogen atom,(ii) a cyano group,(iii) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynyl group, aC₁₋₈ alkyl-carbonyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₈ aryl group,a C₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈aryl-C₁₋₄ alkyl-carbonyl group, a heterocyclic group (e.g., a 5- to8-membered heteroaryl group containing, as an atom (ring atom)constituting a ring system, 1 to 4 hetero atoms selected from an oxygenatom, an optionally oxidized sulfur atom and a nitrogen atom(preferably, an oxygen atom, a sulfur atom and a nitrogen atom) or asaturated or unsaturated aliphatic heterocyclic group), aheterocycle-C₁₋₄ alkyl group, a heterocycle-carbonyl group or aheterocycle-C₁₋₄ alkyl-carbonyl group, each of which is optionallysubstituted by 1 to 5 substituents selected from substituent group T, or(iv) a carbamoyl group optionally having 1 or 2 C₁₋₈ alkyl group(s)optionally substituted by substituent(s) selected from substituent groupT,wherein the carbamoyl group has two substituents, and they optionallyform, together with the adjacent nitrogen atom, a 3- to 8-memberedsaturated or unsaturated aliphatic heterocyclic group optionallysubstituted by substituent(s) selected from substituent group T,R² is (i) a hydrogen atom,(ii) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynyl group, aC₁₋₈ alkyl-carbonyl group, a C₁₋₈ alkylsulfonyl group, a C₃₋₈ cycloalkylgroup, a C₆₋₁₈ aryl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈aryl-carbonyl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group, a C₆₋₁₈aryl-sulfonyl group, a heterocyclic group, a heterocycle-C₁₋₄ alkylgroup, a heterocycle-carbonyl group or a heterocycle-C₁₋₄ alkyl-carbonylgroup, each of which is optionally substituted by 1 to 5 substituentsselected from substituent group T, or(iii) a carbamoyl group optionally having 1 or 2 C₁₋₈ alkyl group(s)optionally substituted by substituent(s) selected from substituent groupT,wherein the carbamoyl group has two substituents, and they optionallyform, together with the adjacent nitrogen atom, a 3- to 8-memberedsaturated or an unsaturated aliphatic heterocyclic group, which isoptionally substituted by substituent(s) selected from substituent groupT, or R¹ and R², or R² and R³ are optionally bonded to form a saturatedor unsaturated 4- to 8-membered heterocycle optionally substituted by 1to 5 substituents selected from substituent group T,[59] the compound of the above-mentioned [15], whereinR^(1a) is (i) a hydrogen atom or(ii) a group represented by the formula —X²—R⁴,wherein X² is a single bond, —NH— or —O—, andR⁴ is (i) a hydrogen atom,(ii) a cyano group,(iii) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynyl group, aC₁₋₈ alkyl-carbonyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₈ aryl group,a C₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈aryl-C₁₋₄ alkyl-carbonyl group, a heterocyclic group (e.g., a 5- to8-membered heteroaryl group containing, as an atom (ring atom)constituting a ring system, 1 to 4 hetero atoms selected from an oxygenatom, an optionally oxidized sulfur atom and a nitrogen atom(preferably, an oxygen atom, a sulfur atom and a nitrogen atom) or asaturated or unsaturated aliphatic heterocyclic group), aheterocycle-C₁₋₄ alkyl group, a heterocycle-carbonyl group or aheterocycle-C₁₋₄ alkyl-carbonyl group, each of which is optionallysubstituted by 1 to 5 substituents selected from substituent group T, or(iv) a carbamoyl group optionally having 1 or 2 C₁₋₈ alkyl group(s)optionally substituted by substituent(s) selected from substituent groupT,wherein the carbamoyl group has two substituents, and they optionallyform, together with the adjacent nitrogen atom, a 3- to 8-memberedsaturated or an unsaturated aliphatic heterocyclic group, which isoptionally substituted by substituent(s) selected from substituent groupT, R^(2a) is (i) a hydrogen atom,(ii) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynyl group, aC₁₋₈ alkyl-carbonyl group, a C₁₋₈ alkylsulfonyl group, a C₃₋₈ cycloalkylgroup, a C₆₋₁₈ aryl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈aryl-carbonyl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group, a C₆₋₁₈aryl-sulfonyl group, a heterocyclic group, a heterocycle-C₁₋₄ alkylgroup, a heterocycle-carbonyl group or a heterocycle-C₁₋₄ alkyl-carbonylgroup, each of which is optionally substituted by 1 to 5 substituentsselected from substituent group T, or(iii) a carbamoyl group optionally having 1 or 2 C₁₋₈ alkyl group(s)optionally substituted by substituent(s) selected from substituent groupT,wherein the carbamoyl group has two substituents, and they optionallyform, together with the adjacent nitrogen atom, a 3- to 8-memberedsaturated or an unsaturated aliphatic heterocyclic group, which isoptionally substituted by substituent(s) selected from substituent groupT, or R^(1a) and R^(2a), or R^(2a) and R^(3a) are optionally bonded toform a saturated or unsaturated 4- to 8-membered heterocycle optionallysubstituted by 1 to 5 substituents selected from substituent group T,R^(3a) is (i) a hydrogen atom, or (ii) a C₁₋₈ alkyl group, a C₂₋₈alkenyl group, a C₂₋₈ alkynyl group or a C₃₋₈ cycloalkyl group, each ofwhich is optionally substituted by 1 to 3 substituents selected fromhalogen, hydroxy, C₁₋₄ alkyloxy, C₁₋₄ alkyl-carbonyl, carboxy, C₁₋₄alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C₁₋₄alkyl-carbonylamino, C₁₋₄ alkoxy-carbonylamino and C₁₋₄alkylsulfonylamino, orR^(3a) is optionally bonded to a carbon atom of the adjacent phenylgroup to form a saturated or unsaturated 4- to 8-memberednitrogen-containing heterocycle, which is optionally substituted by 1 to3 substituents selected from halogen, hydroxy, C₁₋₄ alkyloxy, C₁₋₄alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano, carbamoyl,sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino,B^(a) is a benzene ring optionally substituted by 1 to 5 substituentsselected from halogen, optionally halogenated C₁₋₄ alkyl, hydroxy,optionally halogenated C₁₋₄ alkyloxy, C₁₋₄ alkyloxymethyl, hydroxy-C₁₋₄alkyl, C₁₋₄ alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano,carbamoyl, sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino, andC^(a) is a C₆₋₁₈ aryl group optionally substituted by 1 to 5substituents selected from halogen, optionally halogenated C₁₋₄ alkyl,hydroxy, optionally halogenated C₁₋₄ alkyloxy, C₁₋₄ alkyloxymethyl,hydroxy-C₂₋₄ alkyl, C₁₋₄ alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl,cyano, carbamoyl, sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino,C₁₋₄ alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino,[60] the compound of the above-mentioned [16], whereinR^(1b) is (i) a hydrogen atom or(ii) a group represented by the formula —X²—R⁴,wherein X² is a single bond, —NH— or —O—, andR⁴ is (i) a hydrogen atom,(ii) a cyano group,(iii) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynyl group, aC₁₋₈ alkyl-carbonyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₈ aryl group,a C₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈aryl-C₁₋₄ alkyl-carbonyl group, a heterocyclic group (e.g., a 5- to8-membered heteroaryl group containing, as an atom (ring atom)constituting a ring system, 1-4 hetero atoms selected from an oxygenatom, an optionally oxidized sulfur atom and a nitrogen atom(preferably, an oxygen atom, a sulfur atom and a nitrogen atom) or asaturated or unsaturated aliphatic heterocyclic group), aheterocycle-C₁₋₄ alkyl group, a heterocycle-carbonyl group or aheterocycle-C₁₋₄ alkyl-carbonyl group, each of which is optionallysubstituted by 1 to 5 substituents selected from substituent group T, or(iv) a carbamoyl group optionally having 1 or 2 C₁₋₈ alkyl group(s)optionally substituted by substituent(s) selected from substituent groupT,wherein the carbamoyl group has two substituents, and they optionallyform, together with the adjacent nitrogen atom, a 3- to 8-memberedsaturated or an unsaturated aliphatic heterocyclic group, which isoptionally substituted by substituent(s) selected from substituent groupT,R^(2b) is (i) a hydrogen atom,(ii) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynyl group, aC₁₋₈ alkyl-carbonyl group, a C₁₋₈ alkylsulfonyl group, a C₃₋₈ cycloalkylgroup, a C₆₋₁₈ aryl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈aryl-carbonyl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group, a C₆₋₁₈aryl-sulfonyl group, a heterocyclic group, a heterocycle-C₁₋₄ alkylgroup, a heterocycle-carbonyl group or a heterocycle-C₁₋₄ alkyl-carbonylgroup, each of which is optionally substituted by 1 to 5 substituentsselected from substituent group T, or(iii) a carbamoyl group optionally having 1 or 2 C₁₋₈ alkyl group(s)optionally substituted by substituent(s) selected from substituent groupT,wherein the carbamoyl group has two substituents, and they optionallyform, together with the adjacent nitrogen atom, a 3- to 8-memberedsaturated or an unsaturated aliphatic heterocyclic group, which isoptionally substituted by substituent(s) selected from substituent groupT, orR^(1b) and R^(2b), or R^(2b) and R^(3b) are optionally bonded to form asaturated or unsaturated 4- to 8-membered heterocycle optionallysubstituted by 1 to 5 substituents selected from substituent group T,R^(3b) is (i) a hydrogen atom, or (ii) a C₁₋₈ alkyl group, a C₂₋₈alkenyl group, a C₂₋₈ alkynyl group or a C₃₋₈ cycloalkyl group, each ofwhich is optionally substituted by 1 to 3 substituents selected fromhalogen, hydroxy, C₁₋₄ alkyloxy, C₁₋₄ alkyl-carbonyl, carboxy, C₁₋₄alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C₁₋₄alkyl-carbonylamino, C₁₋₄ alkoxy-carbonylamino and C₁₋₄alkylsulfonylamino, orR^(3b) is optionally bonded to a carbon atom of the adjacent phenylgroup to form a saturated or unsaturated 4- to 8-memberednitrogen-containing heterocycle, which is optionally substituted by 1 to3 substituents selected from halogen, hydroxy, C₁₋₄ alkyloxy, C₁₋₄alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano, carbamoyl,sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino,B^(b) is a benzene ring optionally substituted by 1 to 5 substituentsselected from halogen, optionally halogenated C₁₋₄ alkyl, hydroxy,optionally halogenated C₁₋₄ alkyloxy, C₁₋₄ alkyloxymethyl, hydroxy-C₁₋₄alkyl, C₁₋₄ alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano,carbamoyl, sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino,C^(b) is a C₆₋₁₈ aryl group optionally substituted by 1 to 5substituents selected from halogen, optionally halogenated C₁₋₄ alkyl,hydroxy, optionally halogenated C₁₋₄ alkyloxy, C₁₋₄ alkyloxymethyl,hydroxy-C₁₋₄ alkyl, C₁₋₄ alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl,cyano, carbamoyl, sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino,C₁₋₄ alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino, andZ^(b) is a C₁₋₃ alkylene group optionally substituted by 1 to 3substituents selected from halogen, hydroxy, C₁₋₄ alkyloxy, C₁₋₄alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano, carbamoyl,sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino,[61] the compound of the above-mentioned [17], whereinR^(1c) is (i) a hydrogen atom or(ii) a group represented by the formula —X²—R⁴,wherein X² is a single bond, —NH— or —O—, andR⁴ is (i) a hydrogen atom,(ii) a cyano group,(iii) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynyl group, aC₁₋₈ alkyl-carbonyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₈ aryl group,a C₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈aryl-C₁₋₄ alkyl-carbonyl group, a heterocyclic group (e.g., a 5- to8-membered heteroaryl group containing, as an atom (ring atom)constituting a ring system, 1 to 4 hetero atoms selected from an oxygenatom, an optionally oxidized sulfur atom and a nitrogen atom(preferably, an oxygen atom, a sulfur atom and a nitrogen atom) or asaturated or unsaturated aliphatic heterocyclic group), aheterocycle-C₁₋₄ alkyl group, a heterocycle-carbonyl group or aheterocycle-C₁₋₄ alkyl-carbonyl group, each of which is optionallysubstituted by 1 to 5 substituents selected from substituent group T, or(iv) a carbamoyl group optionally having 1 or 2 C₁₋₈ alkyl group(s)optionally substituted by substituent(s) selected from substituent groupT,wherein the carbamoyl group has two substituents, and they optionallyform, together with the adjacent nitrogen atom, a 3- to 8-memberedsaturated or an unsaturated aliphatic heterocyclic group, which isoptionally substituted by substituent(s) selected from substituent groupT,R^(2c) is (i) a hydrogen atom,(ii) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynyl group, aC₁₋₈ alkyl-carbonyl group, a C₁₋₈ alkylsulfonyl group, a C₃₋₈ cycloalkylgroup, a C₆₋₁₈ aryl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈aryl-carbonyl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group, a C₆₋₁₈aryl-sulfonyl group, a heterocyclic group, a heterocycle-C₁₋₄ alkylgroup, a heterocycle-carbonyl group or a heterocycle-C₁₋₄ alkyl-carbonylgroup, each of which is optionally substituted by 1 to 5 substituentsselected from substituent group T, or(iii) a carbamoyl group optionally having 1 or 2 C₁₋₈ alkyl group(s)optionally substituted by substituent(s) selected from substituent groupT,wherein the carbamoyl group has two substituents, and they optionallyform, together with the adjacent nitrogen atom, a 3- to 8-memberedsaturated or an unsaturated aliphatic heterocyclic group, which isoptionally substituted by substituent(s) selected from substituent groupT, orR^(1c) and R^(2c), or R^(2c) and R^(3c) are optionally bonded to form asaturated or unsaturated 4- to 8-membered heterocycle optionallysubstituted by 1 to 5 substituents selected from substituent group T,R^(3c) is (i) a hydrogen atom, or (ii) a C₁₋₈ alkyl group, a C₂₋₈alkenyl group, a C₂₋₈ alkynyl group or a C₃₋₈ cycloalkyl group, each ofwhich is optionally substituted by 1 to 3 substituents selected fromhalogen, hydroxy, C₁₋₄ alkyloxy, C₁₋₄ alkyl-carbonyl, carboxy, C₁₋₄alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C₁₋₄alkyl-carbonylamino, C₁₋₄ alkoxy-carbonylamino and C₁₋₄alkylsulfonylamino, orR^(3c) is optionally bonded to a carbon atom of the adjacent phenylgroup to form a saturated or unsaturated 4- to 8-memberednitrogen-containing heterocycle, which is optionally substituted by 1 to3 substituents selected from halogen, hydroxy, C₁₋₄ alkyloxy, C₁₋₄alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano, carbamoyl,sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino,B^(c) is a benzene ring optionally substituted by 1 to 5 substituentsselected from halogen, optionally halogenated C₁₋₄ alkyl, hydroxy,optionally halogenated-C₁₋₄ alkyloxy, C₁₋₄ alkyloxymethyl, hydroxy-C₁₋₄alkyl, C₁₋₄ alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano,carbamoyl, sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino, andC^(c) is a 5- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and an optionallyoxidized sulfur atom, which is optionally substituted by 1 to 5substituents selected from halogen, optionally halogenated C₁₋₄ alkyl,hydroxy, optionally halogenated C₁₋₄ alkyloxy, C₁₋₄ alkyloxymethyl,hydroxy-C₁₋₄ alkyl, C₁₋₄ alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl,cyano, carbamoyl, sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino,C₁₋₄ alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino,[62] the compound of the above-mentioned [18], whereinR^(1d) is (i) a hydrogen atom or(ii) a group represented by the formula —X²—R⁴,wherein X² is a single bond, —NH— or —O—, andR⁴ is (i) a hydrogen atom,(ii) a cyano group,(iii) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynyl group, aC₁₋₈ alkyl-carbonyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₈ aryl group,a C₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈aryl-C₁₋₄ alkyl-carbonyl group, a heterocyclic group (e.g., a 5- to8-membered heteroaryl group containing, as an atom (ring atom)constituting a ring system, 1 to 4 hetero atoms selected from an oxygenatom, an optionally oxidized sulfur atom and a nitrogen atom(preferably, an oxygen atom, a sulfur atom and a nitrogen atom) or asaturated or unsaturated aliphatic heterocyclic group), aheterocycle-C₁₋₄ alkyl group, a heterocycle-carbonyl group or aheterocycle-C₁₋₄ alkyl-carbonyl group, each of which is optionallysubstituted by 1 to 5 substituents selected from substituent group T, or(iv) a carbamoyl group optionally having 1 or 2 C₁₋₈ alkyl group(s)optionally substituted by substituent(s) selected from substituent groupT,wherein the carbamoyl group has two substituents, and they optionallyform, together with the adjacent nitrogen atom, a 3- to 8-memberedsaturated or an unsaturated aliphatic heterocyclic group, which isoptionally substituted by substituent(s) selected from substituent groupT,R^(2d) is (i) a hydrogen atom,(ii) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynyl group, aC₁₋₈ alkyl-carbonyl group, a C₁₋₈ alkylsulfonyl group, a C₃₋₈ cycloalkylgroup, a C₆₋₁₈ aryl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈aryl-carbonyl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group, a C₆₋₁₈aryl-sulfonyl group, a heterocyclic group, a heterocycle-C₁₋₄ alkylgroup, a heterocycle-carbonyl group or a heterocycle-C₁₋₄ alkyl-carbonylgroup, each of which is optionally substituted by 1 to 5 substituentsselected from substituent group T, or(iii) a carbamoyl group optionally having 1 or 2 C₁₋₈ alkyl group(s)optionally substituted by substituent(s) selected from substituent groupT,wherein the carbamoyl group has two substituents, and they optionallyform, together with the adjacent nitrogen atom, a 3- to 8-memberedsaturated or an unsaturated aliphatic heterocyclic group, which isoptionally substituted by substituent(s) selected from substituent groupT, orR^(1d) and R^(2d), or R^(2d) and R^(3d) are optionally bonded to form asaturated or unsaturated 4- to 8-membered heterocycle optionallysubstituted by 1 to 5 substituents selected from substituent group T,R^(3d) is (i) a hydrogen atom, or(ii) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynyl group or aC₃₋₈ cycloalkyl group, each of which is optionally substituted by 1 to 3substituents selected from halogen, hydroxy, C₁₋₄ alkyloxy, C₁₋₄alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano, carbamoyl,sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino, orR^(3d) is optionally bonded to a carbon atom of the adjacent phenylgroup to form a saturated or unsaturated 4- to 8-memberednitrogen-containing heterocycle, which is optionally substituted by 1 to3 substituents selected from halogen, hydroxy, C₁₋₄ alkyloxy, C₁₋₄alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano, carbamoyl,sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino, Bd is a benzene ringoptionally substituted by 1 to 5 substituents selected from halogen,optionally halogenated C₁₋₄ alkyl, hydroxy, optionally halogenated C₁₋₄alkyloxy, C₁₋₄ alkyloxymethyl, hydroxy-C₁₋₄ alkyl, C₁₋₄ alkyl-carbonyl,carboxy, C₁₋₄ alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro,amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄ alkoxy-carbonylamino and C₁₋₄alkylsulfonylamino,C^(d) is a 5- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and an optionallyoxidized sulfur atom, which is optionally substituted by 1 to 5substituents selected from halogen, optionally halogenated C₁₋₄ alkyl,hydroxy, optionally halogenated C₁₋₄ alkyloxy, C₁₋₄ alkyloxymethyl,hydroxy-C₁₋₄ alkyl, C₁₋₄ alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl,cyano, carbamoyl, sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino,C₁₋₄ alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino, and Z^(d) is aC₁₋₃ alkylene group optionally substituted by 1 to 3 substituentsselected from halogen, hydroxy, C₁₋₄ alkyloxy, C₁₋₄ alkyl-carbonyl,carboxy, C₁₋₄ alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro,amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄ alkoxy-carbonylamino and C₁₋₄alkylsulfonylamino,[63] the compound of the above-mentioned [19], whereinR^(2e) is (i) a hydrogen atom,(ii) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynyl group, aC₁₋₈ alkyl-carbonyl group, a C₁₋₈ alkylsulfonyl group, a C₃₋₈ cycloalkylgroup, a C₆₋₁₈ aryl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈aryl-carbonyl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group, a C₆₋₁₈aryl-sulfonyl group, a heterocyclic group, a heterocycle-C₁₋₄ alkylgroup, a heterocycle-carbonyl group or a heterocycle-C₁₋₄ alkyl-carbonylgroup, each of which is optionally substituted by 1 to 5 substituentsselected from substituent group T, or(iii) a carbamoyl group optionally having 1 or 2 C₁₋₈ alkyl group(s)optionally substituted by substituent(s) selected from substituent groupT,wherein the carbamoyl group has two substituents, and they optionallyform, together with the adjacent nitrogen atom, a 3- to 8-memberedsaturated or an unsaturated aliphatic heterocyclic group, which isoptionally substituted by substituent(s) selected from substituent groupT, orR^(2e) and R^(3e) are optionally bonded to form a saturated orunsaturated 4- to 8-membered heterocycle optionally substituted by 1 to5 substituents selected from substituent group T,R^(3e) is (i) a hydrogen atom, or(ii) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynyl group or aC₃₋₈ cycloalkyl group, each of which is optionally substituted by 1 to 3substituents selected from halogen, hydroxy, C₁₋₄ alkyloxy, C₁₋₄alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano, carbamoyl,sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino, orR^(3e) is optionally bonded to a carbon atom of the adjacent phenylgroup to form a saturated or unsaturated 4- to 8-memberednitrogen-containing heterocycle, which is optionally substituted by 1 to3 substituents selected from halogen, hydroxy, C₁₋₄ alkyloxy, C₁₋₄alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano, carbamoyl,sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino,B^(e) is a benzene ring optionally substituted by 1 to 5 substituentsselected from halogen, optionally halogenated C₁₋₄ alkyl, hydroxy,optionally halogenated C₁₋₄ alkyloxy, C₁₋₄ alkyloxymethyl, hydroxy-C₁₋₄alkyl, C₁₋₄ alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano,carbamoyl, sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino, andC^(e) is a C₆₋₁₈ aryl group optionally substituted by 1 to 5substituents selected from halogen, optionally halogenated C₁₋₄ alkyl,hydroxy, optionally halogenated C₁₋₄ alkyloxy, C₁₋₄ alkyloxymethyl,hydroxy-C₁₋₄ alkyl, C₁₋₄ alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl,cyano, carbamoyl, sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino,C₁₋₄ alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino,[64] the compound of the above-mentioned [20], whereinR^(f) is (i) a hydrogen atom,(ii) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynyl group, aC₁₋₈ alkyl-carbonyl group, a C₁₋₈ alkylsulfonyl group, a C₃₋₈ cycloalkylgroup, a C₆₋₁₈ aryl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈aryl-carbonyl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group, a C₆₋₁₈aryl-sulfonyl group, a heterocyclic group, a heterocycle-C₁₋₄ alkylgroup, a heterocycle-carbonyl group or a heterocycle-C₁₋₄ alkyl-carbonylgroup, each of which is optionally substituted by 1 to 5 substituentsselected from substituent group T, or(iii) a carbamoyl group optionally having 1 or 2 C₁₋₈ alkyl group(s)optionally substituted by substituent(s) selected from substituent groupT,wherein the carbamoyl group has two substituents, and they optionallyform, together with the adjacent nitrogen atom, a 3- to 8-memberedsaturated or an unsaturated aliphatic heterocyclic group, which isoptionally substituted by substituent(s) selected from substituent groupT, orR^(2f) and R^(3f) are optionally bonded to form a saturated orunsaturated 4- to 8-membered heterocycle optionally substituted by 1 to5 substituents selected from substituent group T, R^(3f) is (i) ahydrogen atom, or (ii) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈alkynyl group or a C₃₋₈ cycloalkyl group, each of which is optionallysubstituted by 1 to 3 substituents selected from halogen, hydroxy, C₁₋₄alkyloxy, C₁₋₄ alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano,carbamoyl, sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino, orR^(3f) is optionally bonded to a carbon atom of the adjacent phenylgroup to form a saturated or unsaturated 4- to 8-memberednitrogen-containing heterocycle, which is optionally substituted by 1 to3 substituents selected from halogen, hydroxy, C₁₋₄ alkyloxy, C₁₋₄alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano, carbamoyl,sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino,B^(f) is a benzene ring optionally substituted by 1 to 5 substituentsselected from halogen, optionally halogenated C₁₋₄ alkyl, hydroxy,optionally halogenated C₁₋₄ alkyloxy, C₁₋₄ alkyloxymethyl, hydroxy-C₁₋₄alkyl, C₁₋₄ alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano,carbamoyl, sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino,C^(f) is a C₆₋₁₈ aryl group optionally substituted by 1 to 5substituents selected from halogen, optionally halogenated C₁₋₄ alkyl,hydroxy, optionally halogenated C₁₋₄ alkyloxy, C₁₋₄ alkyloxymethyl,hydroxy-C₁₋₄ alkyl, C₁₋₄ alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl,cyano, carbamoyl, sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino,C₁₋₄ alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino, andZ^(f) is a C₁₋₃ alkylene group optionally substituted by 1 to 3substituents selected from halogen, hydroxy, C₁₋₄ alkyloxy, C₁₋₄alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano, carbamoyl,sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino,[65] the compound of the above-mentioned [21], whereinR^(2g) is (i) a hydrogen atom,(ii) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynyl group, aC₁₋₈ alkyl-carbonyl group, a C₁₋₈ alkylsulfonyl group, a C₃₋₈ cycloalkylgroup, a C₆₋₁₈ aryl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈aryl-carbonyl group, a C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group, a C₆₋₁₈aryl-sulfonyl group, a heterocyclic group, a heterocycle-C₁₋₄ alkylgroup, a heterocycle-carbonyl group or a heterocycle-C₁₋₄ alkyl-carbonylgroup, each of which is optionally substituted by 1 to 5 substituentsselected from substituent group T, or(iii) a carbamoyl group optionally having 1 or 2 C₁₋₈ alkyl group(s)optionally substituted by substituent(s) selected from substituent groupT,wherein the carbamoyl group has two substituents, and they optionallyform, together with the adjacent nitrogen atom, a 3- to 8-memberedsaturated or an unsaturated aliphatic heterocyclic group, which isoptionally substituted by substituent(s) selected from substituent groupT, orR^(2g) and R^(3g) are optionally bonded to form a saturated orunsaturated 4- to 8-membered heterocycle optionally substituted by 1 to5 substituents selected from substituent group T,R^(3g) is (i) a hydrogen atom, or(ii) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynyl group or aC₃₋₈ cycloalkyl group, each of which is optionally substituted by 1 to 3substituents selected from halogen, hydroxy, C₁₋₄ alkyloxy, C₁₋₄alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano, carbamoyl,sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino, orR^(3g) is optionally bonded to a carbon atom of the adjacent phenylgroup to form a saturated or unsaturated 4- to 8-memberednitrogen-containing heterocycle optionally substituted by 1 to 3substituents selected from halogen, hydroxy, C₁₋₄ alkyloxy, C₁₋₄alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano, carbamoyl,sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino,B^(g) is a benzene ring optionally substituted by 1 to 5 substituentsselected from halogen, optionally halogenated C₁₋₄ alkyl, hydroxy,optionally halogenated C₁₋₄ alkyloxy, C₁₋₄ alkyloxymethyl, hydroxy-C₁₋₄alkyl, C₁₋₄ alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano,carbamoyl, sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino,C^(g) is a 5- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and an optionallyoxidized sulfur atom, which is optionally substituted by 1 to 5substituents selected from halogen, optionally halogenated C₁₋₄ alkyl,hydroxy, optionally halogenated C₁₋₄ alkyloxy, C₁₋₄ alkyloxymethyl,hydroxy-C₁₋₄ alkyl, C₁₋₄ alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl,cyano, carbamoyl, sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino,C₁₋₄ alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino, and the like.

According to the present invention, a fused pyrimidine compound having asuperior tyrosine kinase inhibitory action, which is low toxic andhighly satisfactory as a pharmaceutical product, a production methodthereof and use thereof can be provided.

In the present specification, unless otherwise specified, the “aryl” inthe “aryl group” and the substituents includes a monocyclic aryl groupand a fused polycyclic aryl group. As the “aryl group”, for example, aC₆₋₁₈ aryl group can be mentioned. As the “C₆₋₁₈ aryl group”, forexample, phenyl, biphenylyl, naphthyl, anthryl, phenanthryl andacenaphthylenyl can be mentioned.

In the present specification, as the “heterocyclic group” (and“heterocycle-” in the substituents), for example, a 5- to 8-memberedheteroaryl group or a saturated or unsaturated aliphatic heterocyclicgroup containing, as an atom (ring atom) constituting a ring system, oneor more (preferably 1 to 4, more preferably 1 or 2) hetero atomsselected from an oxygen atom, an optionally oxidized sulfur atom and anitrogen atom and the like (preferably, an oxygen atom, a sulfur atomand a nitrogen atom etc.) can be mentioned.

In the present specification, unless otherwise specified, as the“aliphatic hydrocarbon group”, a linear or branched aliphatichydrocarbon group having 1 to 15 carbon atom (preferably, 1 to 8 carbonatom) can be mentioned. As such “aliphatic hydrocarbon group”, forexample, a ClB alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynyl group,a C₃₋₈ cycloalkyl group and the like can be mentioned.

In the present specification, unless otherwise specified, as the“heteroaryl group”, an aromatic monocyclic heterocyclic group (e.g., 5-or 6-membered aromatic monocyclic heterocyclic group such as furyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like)and an aromatic fused heterocyclic group (e.g., 8 to 12-memberedaromatic fused heterocyclic group such as benzofuranyl, isobenzofuranyl,benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl,benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, benzopyranyl,1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl,purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,γ-carbolinyl, acrydinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxathiinyl, thianthrenyl, phenathridinyl, phenathrolinyl,indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl and the like) and the like can bementioned. As the aromatic fused heterocyclic group, a heterocyclewherein the aforementioned 5- or 6-membered aromatic monocyclicheterocyclic group is fused with a benzene ring and a heterocyclewherein the same or different two heterocycles of the aforementioned 5-or 6-membered aromatic monocyclic heterocyclic group are fused arepreferable.

In the present specification, unless otherwise specified, as the“aliphatic heterocyclic group”, for example, a 3- to 8-membered(preferably 5- or 6-membered) saturated or unsaturated (preferablysaturated) aliphatic heterocyclic group such as oxiranyl, azetidinyl,oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl,piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl,dihydro-1,2,4-oxadiazolyl and the like, and the like can be mentioned.

In the present specification, unless otherwise specified, as the “C₁₋₈alkyl group”, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neopentyl,n-hexyl, i-hexyl, n-heptyl and n-octyl and the like can be mentioned,with preference given to a C₁₋₆ alkyl group. In the presentspecification, moreover, unless otherwise specified, as the “C₁₋₄ alkylgroup”, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl andi-butyl can be mentioned.

In the present specification, unless otherwise specified, as the “C₂₋₈alkenyl group”, for example, vinyl, (1- or 2-)propenyl, (1-, 2- or3-)butenyl, pentenyl, octenyl and (1,3-)butadienyl can be mentioned,with preference given to a C₂₋₄ alkenyl group.

In the present specification, unless otherwise specified, as the “C₂₋₈alkynyl group”, for example, ethynyl, (1- or 2-)propynyl, (1-, 2- or3-)butynyl, pentynyl and octynyl can be mentioned, with preference givento a C₂₋₄ alkynyl group.

In the present specification, unless otherwise specified, as the “C₃₋₈cycloalkyl group”, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl can be mentioned, with preferencegiven to a C₃₋₆ cycloalkyl group.

In the present specification, unless otherwise specified, as the “C₁₋₄alkylene”, for example, methylene, ethylene, trimethylene,tetramethylene and propylene and the like can be mentioned.

In the present specification, unless otherwise specified, as the“—O—(C₁₋₄ alkylene)—”, for example, —OCH₂—, —OCH₂CH₂—, —OCH₂)₃—,—O(CH₂)₄—, —OCH(CH₃)—, —OC(CH₃)₂—, —OCH(CH₃) CH₂—, —OCH₂CH(CH₃)—,—OC(CH₃)₂CH₂— and —OCH₂C(CH₃)₂— and the like can be mentioned.

In the present specification, unless otherwise specified, as the “C₆₋₁₈aryl-carbonyl group”, for example, benzoyl, naphthoyl, anthrylcarbonyl,phenanthrylcarbonyl and acenaphthylenylcarbonyl and the like can bementioned.

In the present specification, unless otherwise specified, as the “C₆₋₁₈aryl-C₁₋₄ alkyl-carbonyl group”, for example, benzylcarbonyl,3-phenylpropionyl, 2-phenylpropionyl, 4-phenylbutyryl and5-phenylpentanoyl and the like can be mentioned.

In the present specification, unless otherwise specified, as the“halogen”, fluorine, chlorine, bromine and iodine can be mentioned.

As the “5- to 8-membered heterocycle-carbonyl group containing 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfuratom”, “a 5- to 8-membered cyclic amino-carbonyl group optionally having1 or 2 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom” is preferable, for example, pyrrolidin-1-ylcarbonyl,piperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl, morpholin-4-ylcarbonyl,thiomorpholin-4-ylcarbonyl and the like can be mentioned.

In the above-mentioned formula, as the “aryl group” for A, a C₆₋₁₈ arylgroup is preferable, and phenyl is more preferable.

The “aryl group” is optionally substituted by a group of the formula—Y²—B, wherein Y² is a single bond, —O—, —O—(C₁₋₃ alkylene)-(preferably—OCH₂—), —NH— or —S—, and B is an aryl group, a heterocyclic group, aC₃₋₈ cycloalkyl group, a carbamoyl group, a ureido group, a C₆₋₁₈aryl-carbonyl group or a C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group, each ofwhich is optionally substituted.

As Y², a single bond, —O— or —OCH₂— is preferable, and —O— or —OCH₂— ismore preferable.

As the “aryl group” for B, a C₆₋₁₈ aryl group is preferable, and phenylis more preferable.

As the “heterocyclic group” for B, the aforementioned “5 or 6-memberedaromatic monocyclic heterocyclic group” is preferable, and pyridyl ismore preferable.

The “aryl group”, “heterocyclic group”, “C₆₋₁₈ aryl-carbonyl group” or“C₆-18 aryl-C₁₋₄ alkyl-carbonyl group” for B may have, for example, 1 to5, the same or different substituents selected from halogen, optionallyhalogenated C₁₋₄ alkyl, hydroxy, optionally halogenated C₁₋₄ alkyloxy,C₁₋₄ alkyloxymethyl, hydroxy-C₁₋₄ alkyl, C₁₋₄ alkyl-carbonyl, carboxy,C₁₋₄ alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C₁₋₄alkyl-carbonylamino, C₁₋₄ alkoxy-carbonylamino and C₁₋₄alkylsulfonylamino, at any substitutable position(s).

The “aryl group” for A may have, besides a group of the above-mentionedformula —Y²—B, 1 to 5, the same or different substituents at anysubstitutable position(s). As such substituent, substituents similar tothose exemplified for “aryl group” or “heterocyclic group” for B can bementioned.

As the “aliphatic hydrocarbon group” for R³, a C₁₋₈ alkyl group, a C₂₋₈alkenyl group, a C₂₋₈ alkynyl group and a C₃₋₈ cycloalkyl group arepreferable.

The “aliphatic hydrocarbon group” for R³ is optionally substituted by 1to 3 substituents selected from halogen, hydroxy, C₁₋₄ alkyloxy, C₁₋₄alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano, carbamoyl,sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino.

The “C₁₋₄ alkylene” and “—O—(C₁₋₄ alkylene)-” for Y¹ are optionallysubstituted by 1 to 3 substituents selected from halogen, hydroxy, C₁₋₄alkyloxy, C₁₋₄ alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano,carbamoyl, sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino.

As X¹, —NR³— wherein R³ is as defined above is preferable.

As the “optionally substituted group bonded via a carbon atom, anitrogen atom or an oxygen atom” for R¹, a group of the formula —X²—R⁴can be mentioned, wherein X² is a single bond, —NH— or —O—, and R⁴ is ahydrogen atom, a cyano group, or a C₁₋₈ alkyl group, a C₂₋₈ alkenylgroup, a C₂₋₈ alkynyl group, a carbamoyl group, a C₁₋₈ alkyl-carbonylgroup, a C₃₋₈ cycloalkyl group, a C₆₋₁₈ aryl group, a C₆₋₁₈ aryl-C₁₋₄alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈ aryl-C₁₋₄alkyl-carbonyl group, a heterocyclic group, a heterocycle-C₁₋₄ alkylgroup, a heterocycle-carbonyl group or a heterocycle-C₁₋₄ alkyl-carbonylgroup, each of which is optionally substituted.

The “C₁₋₈ alkyl group”, “C₂₋₈ alkenyl group”, “C₂₋₈ alkynyl group”,“C₁₋₈ alkyl-carbonyl group”, “C₃₋₈ cycloalkyl group”, “C₆₋₁₈ arylgroup”, “C₆₋₁₈ aryl-C₁₋₄ alkyl group”, “C₆₋₁₈ aryl-carbonyl group”,“C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group”, “heterocyclic group”,“heterocycle-C₁₋₄ alkyl group”, “heterocycle-carbonyl group” and“heterocycle-C₁₋₄ alkyl-carbonyl group” are, for example, optionallysubstituted by one or more (preferably 1 to 5, more preferably 1 to 3)substituent(s) selected from

(a) halogen,(b) oxo,(c) optionally halogenated C₁₋₄ alkyl,(d) —(CH₂)_(m)-Q,(e) —(CH₂)_(m)-Z¹- (optionally halogenated C₁₋₄ alkyl),(f) —(CH₂)_(m)-Z¹-C₃₋₈ cycloalkyl,(g) —(CH₂)_(m)-Z²-(CH₂)_(n)-Q,(h) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹- (optionally halogenated C₁₋₄ alkyl),(i) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹-C₃₋₈ cycloalkyl,(j) —(CH₂)-Z¹- (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom)(k) —(CH₂)_(m)-Z²-C₁₋₄ alkoxy, and(l) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹-(CH₂)_(n)-Z¹-C₁₋₄ alkyl (hereinafter tobe sometimes to be referred to as substituent group T).

In these formulas, m is an integer of 0 to 4, n is an integer of 1 to 4,Q is hydroxy, carboxy, cyano, nitro, —NR⁶R⁷, —CONR⁶R⁷ or —SO₂NR⁶R⁷, Z¹is —O—, —CO—, —C(OH)R⁸—, —C(═N—OR⁸)—, —S—, —SO—, —SO₂—, —N(COR⁸)—,—N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—, —NR⁸—CO₂—,—NR⁸—CO—NH—, —NR⁸—SO₂—, or —NR⁸—C(═NH)—NH—, and Z² is —O—, —CO—,—C(OH)R⁸—, —C(═N—OR⁸)—, —S—, —SO—, —SO₂—, —NR⁸—, —N(COR⁸)—, —N(CO₂R⁹)—,—N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—, —NR⁸—CO₂—, NR⁸—CO—NH—,—NR⁸—C(═NH)—NH—, —NR⁸—SO₂—, or —SO₂—NR⁸—. In these formulas, (CH₂)_(m)and (CH₂)_(n) are optionally substituted by one or more (preferably 1 to5, more preferably 1 to 3) substituents selected from, for example,halogen, optionally halogenated C₁₋₄ alkyl and hydroxy, and when m or nis not less than 2, a subset —CH₂CH₂— of (CH₂)_(m) and (CH₂)_(n) isoptionally replaced by —CH═CH— or —C≡C—.

In these formulas, R⁶ and R⁷ are the same or different and each is ahydrogen atom or C₁₋₄ alkyl, or R⁶ and R⁷ form a ring together with anitrogen atom. In these formulas, moreover, R⁸ is a hydrogen atom orC₁₋₄ alkyl and R⁹ is C₁₋₄ alkyl. When R⁶ and R⁷ form a ring togetherwith a nitrogen atom, as the nitrogen-containing heterocyclic group, forexample, a 3 to 8-membered (preferably 5 or 6-membered) saturated orunsaturated (preferably saturated) aliphatic heterocyclic group such asazetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl,heptamethyleneimino, morpholinyl, thiomorpholinyl, piperazinyl,homopiperazinyl and the like, and the like can be mentioned.

As X², a single bond is preferable.

As R⁴, a hydrogen atom or a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, aC₆₋₁₈ aryl group or heterocyclic group, each of which is optionallysubstituted is preferable. As the “C₆₋₁₈ aryl group” for R⁴, phenyl ispreferable. As the “heterocyclic group” for R⁴, the aforementioned “5 or6-membered aromatic monocyclic heterocyclic group” is preferable, andfuryl is preferable.

As the “optionally substituted group bonded via a carbon atom or asulfur atom” for R², a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈alkynyl group, a carbamoyl group, a C₁₋₈ alkyl-carbonyl group, a C₁₋₈alkylsulfonyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₈ aryl group, aC₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈aryl-C₁₋₄ alkyl-carbonyl group, a C₆₋₁₈ aryl-sulfonyl group, aheterocyclic group, a heterocycle-C₁₋₄ alkyl group, aheterocycle-carbonyl group or a heterocycle-C₁₋₄ alkyl-carbonyl group,each of which is optionally substituted, can be mentioned.

The “C₁₋₈ alkyl group”, “C₂₋₈ alkenyl group”, “C₂₋₈ alkynyl group”,“C₁₋₈ alkyl-carbonyl group”, “C₁₋₈ alkylsulfonyl group”, “C₃₋₈cycloalkyl group”, “C₆₋₁₈ aryl group”, “C₆₋₁₈ aryl-C₁₋₄ alkyl group”,“C₆₋₁₈ aryl-carbonyl group”, “C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group”,“C₆₋₁₈ aryl-sulfonyl group”, “heterocyclic group”, “heterocycle-C₁₋₄alkyl group”, “heterocycle-carbonyl group” and “heterocycle-C₁₋₄alkyl-carbonyl group” are optionally substituted by, for example, one ormore (preferably 1 to 5, more preferably 1 to 3) substituents selectedfrom the above-mentioned substituent group T.

As R², a hydrogen atom or a C₁₋₈ alkyl group, a C₆₋₁₈ aryl group, aC₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈aryl-sulfonyl group or heterocycle-C₁₋₄ alkyl group, each of which isoptionally substituted, is preferable.

As the “C₆₋₁₈ aryl group” for R², phenyl is preferable. As the “C₆₋₁₈aryl-C₁₋₄ alkyl group” for R², benzyl is preferable. As the “C₆₋₁₈aryl-carbonyl group” for R², benzoyl is preferable. As the “C₆₋₁₈aryl-sulfonyl group” for R², phenylsulfonyl is preferable. As the“heterocyclic group” or “heterocycle-” of “heterocycle-C₁₋₄ alkylgroup”, “heterocycle-carbonyl group” and “heterocycle-C₁₋₄alkyl-carbonyl group” for R², the aforementioned “5 or 6-memberedaromatic monocyclic heterocyclic group” or the aforementioned “aliphaticheterocyclic group” is preferable, and furyl or tetrahydrofuryl ispreferable.

In the substituents that a group represented by R² may have, when R⁶ andR⁷ form a ring together with a nitrogen atom, the “ring” optionallyfurther has 1 to 5 (preferably 1 to 3) the same or differentsubstituents. As such substituents, substituents similar to thoseexemplified for “aryl group” or “heterocyclic group” for B can bementioned.

The aforementioned “carbamoyl group” and “ureido group” optionally have1 or 2 optionally substituted C₁₋₈ alkyl group(s). Alternatively, the“carbamoyl group” and “ureido group” may have two substituents and theymay form an optionally substituted ring, together with the adjacentnitrogen atom. As the “ring” of the “optionally substituted ring”, ringssimilar to those formed by R⁶ and R⁷ together with a nitrogen atom asexemplified above can be mentioned. As the “substituent” of the“optionally substituted C₁₋₈ alkyl group” and as the “substituent” ofthe “optionally substituted ring”, groups similar to the substituents ofthe above-mentioned substituent group T can be mentioned.

As the “optionally substituted carbamoyl group”, carbamoyl, C₁₋₈alkylcarbamoyl, di(C₁₋₈ alkyl)carbamoyl, C₆₋₁₈ aryl-C₁₋₄ alkylcarbamoyl,azetidin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,piperazin-1-ylcarbonyl, morpholin-4-ylcarbonyl,thiomorpholin-4-ylcarbonyl, (C₁₋₄ alkyl)piperidin-1-ylcarbonyl, (C₆₋₁₈aryl-C₁₋₄ alkyl)piperidin-1-ylcarbonyl and the like can be mentioned.

As the “optionally substituted ureido group”, ureido, 3-(C₁₋₈alkyl)ureido, 3,3-di(C₁₋₈ alkyl)ureido, 3-(C₆₋₁₈ aryl-C₁₋₄ alkyl)ureido,azetidine-1-ylcarbonylamino, pyrrolidin-1-ylcarbonylamino,piperidin-1-ylcarbonylamino, piperazin-1-ylcarbonylamino,morpholin-4-ylcarbonylamino, thiomorpholin-4-ylcarbonylamino, (C₁₋₄alkyl)piperidin-1-ylcarbonylamino, (C₆₋₁₈ aryl-C₁₋₄alkyl)piperidin-1-ylcarbonylamino and the like can be mentioned.

As the “ring structure” of the optionally substituted ring structureformed by R³ bonded to a carbon atom or a hetero atom on the aryl groupor the heteroaryl group represented by A, a saturated or unsaturated(preferably saturated) 4- to 8-membered (preferably 5- or 6-membered)nitrogen-containing heterocycle can be mentioned. Specifically,

The “ring structure” may have 1 to 5 (preferably 1 to 3, more preferably1 or 2) the same or different substituents at any substitutableposition(s). As such substituents, substituents similar to thoseexemplified for “aryl group” or “heterocyclic group” for B can bementioned.

As the “ring structure” of the optionally substituted ring structureformed by R¹ and R² bonded to each other, a saturated or unsaturated(preferably saturated) 4- to 8-membered (preferably 5- or 6-membered)heterocycle can be mentioned. When R¹ and R² are bonded to form anoptionally substituted ring structure, for example,

wherein each symbol is as defined above, and the like can be mentioned.

As the “ring structure” of the optionally substituted ring structureformed by R² and R³ bonded to each other, a saturated or unsaturated(preferably saturated) 4- to 8-membered (preferably 5- to 7-membered)heterocycle can be mentioned. When R² and R³ are bonded to form anoptionally substituted ring structure, for example,

wherein each symbol is as defined above, and the like can be mentioned.The “ring structure” formed by R¹ and R², or R² and R³ bonded to eachother may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) thesame or different substituents selected from the above-mentionedsubstituent group T at any substitutable position(s).

When W is C(R¹), compound (I) is represented by the following formula(IA):

wherein each symbol is as defined above.

When W is N, compound (I) is represented by the following formula (IB)or (IC):

wherein each symbol is as defined above.

Specifically, as compound (I), the following compounds (Ia)-(Ij) and thelike are preferably used.

[Compound (Ia)]

A compound represented by the formula:

wherein R^(1a) is a hydrogen atom or an optionally substituted groupbonded via a carbon atom, a nitrogen atom or an oxygen atom, andR^(2a) is an optionally substituted group bonded via a carbon atom or asulfur atom, orR^(1a) and R^(2a), or R^(2a) and R^(3a) are optionally bonded to form anoptionally substituted ring structure,R^(3a) is a hydrogen atom or an optionally substituted aliphatichydrocarbon group, or R^(3a) is optionally bonded to a carbon atom ofthe adjacent phenyl group to form an optionally substituted ringstructure,B^(a) is an optionally substituted benzene ring, and C^(a) is anoptionally substituted C₆₋₁₈ aryl group, or a salt thereof.

As the “optionally substituted group bonded via a carbon atom, anitrogen atom or an oxygen atom” for R^(1a), those similar to the“optionally substituted group bonded via a carbon atom, a nitrogen atomor an oxygen atom” for R¹ can be used.

As the “optionally substituted group bonded via a carbon atom or asulfur atom” for R^(2a), those similar to the “optionally substitutedgroup bonded via a carbon atom or a sulfur atom” for R² can be used.

As the “optionally substituted ring structure” formed by R^(1a) andR^(2a), or R^(2a) and R^(3a) bonded to each other, those similar to the“optionally substituted ring structure” formed by R¹ and R², or R² andR³ bonded to each other can be used.

As the “optionally substituted aliphatic hydrocarbon group” for R^(3a),those similar to the “optionally substituted aliphatic hydrocarbongroup” for R³ can be used.

As the “optionally substituted ring structure” for R^(3a), which isformed by binding to a carbon atom of the adjacent phenyl group, thosesimilar to the “optionally substituted ring structure” for R³, which isformed by binding to a carbon atom of the adjacent phenyl group can beused.

As the substituent of the “optionally substituted benzene ring” forB^(a), for example, 1 to 5, the same or different substituents selectedfrom halogen, optionally halogenated C₁₋₄ alkyl, hydroxy, optionallyhalogenated C₁₋₄ alkyloxy, C₁₋₄ alkyloxymethyl, hydroxy-C₁₋₄ alkyl, C₁₋₄alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano, carbamoyl,sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino can be used.

As the “C₆₋₁₈ aryl group” of the “optionally substituted C₆₋₁₈ arylgroup” for C^(a), for example, phenyl, biphenylyl, naphthyl, anthryl,phenanthryl, acenaphthylenyl and the like can be used, with preferencegiven to a phenyl group.

As the “substituent” of the “optionally substituted C₆₋₁₈ aryl group”for C^(a), those similar to the substituents of the “optionallysubstituted benzene ring” for B^(a) can be used.

As R^(2a), a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynylgroup, a carbamoyl group, a C₁₋₈ alkyl-carbonyl group, a C₁₋₈alkylsulfonyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₈ aryl group, aC₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈aryl-C₁₋₄ alkyl-carbonyl group, a C₆₋₁₈ aryl-sulfonyl group, aheterocyclic group, a heterocycle-C₁₋₄ alkyl group, aheterocycle-carbonyl group or a heterocycle-C₁₋₄ alkyl-carbonyl group,each of which is optionally substituted by 1 to 5 substituents selectedfrom

(a) halogen,(b) oxo,(c) optionally halogenated C₁₋₄ alkyl,(d) —(CH₂)_(m)-Q,(e) —(CH₂)_(m)-Z¹- (optionally halogenated C₁₋₄ alkyl),(f) —(CH₂)_(n)-Z¹-C₃₋₈ cycloalkyl,(g) —(CH₂)_(m)-Z²-(CH₂)_(n)-Q,(h) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹- (optionally halogenated C₁₋₄ alkyl),(i) —(CH₂)_(m)-Z¹-(CH₂)_(n)-Z¹-C₃₋₈ cycloalkyl,(j) —(CH₂)_(m)-Z¹- (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom),(k) —(CH₂)_(m)-Z²-C₁₋₄ alkoxy, and(l) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹-(CH₂)_(n)-Z¹-C₁₋₄ alkylwherein m is an integer of 0 to 4, n is an integer of 1 to 4,Q is hydroxy, carboxy, cyano, nitro, —NR⁶R⁷, —CONR⁶R⁷, —OCONH₂ or—SO₂NR⁶R⁷,Z¹ is —O—, —CO—, —C(OH)R⁸—, —C(═N—OR⁸)—, —S—, SO—, —SO₂—, —N(COR⁹)—,—N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁹—NR⁸—CO—, —NR⁸—CO₂—,—NR⁸—CO—NH—, —NR⁸—SO₂—, or —NR⁸—C(═NH)—NH—,Z² is —O, —CO—, —C(OH)R⁸—, —C(═N—OR)—, —S—, —SO—, —SO₂—, —NR⁹—,—N(COR⁸)—, —N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—,—NR⁸—CO₂—, —NR⁸—CO—NH—, —NR⁸—C(═NH)—NH—, —NR⁸—SO₂—, or —SO₂—NR⁸—,(CH₂)_(m) and (CH₂), are optionally substituted by 1 to 5 substituentsselected from halogen, optionally halogenated C₁₋₄ alkyl and hydroxy,and when m or n is not less than 2, a subset —CH₂CH₂— of (CH₂)_(m) and(CH₂)_(n) is optionally replaced by —CH═CH— or —C≡C—,R⁶ and R⁷ are the same or different and each is a hydrogen atom or aC₁₋₄ alkyl group, or R⁶ and R⁷ are bonded to form, together with anitrogen atom, a 3- to 8-membered saturated or unsaturated aliphaticheterocyclic group,R⁸ is a hydrogen atom or C₁₋₄ alkyl, and R⁹ is C₁₋₄ alkyl, ispreferable.

As compound (Ia), a compound wherein

B^(a) is a benzene ring optionally substituted by 1 to 4 substituentsselected from halogen, C₁₋₄ alkyl, hydroxy-C₁₋₄ alkyl and C₁₋₄ alkyloxy;C^(a) is a phenyl group optionally substituted by 1 to 5 substituentsselected from (i) halogen, (ii) optionally halogenated C₁₋₄ alkyl, (iii)hydroxy-C₁₋₄ alkyl, (iv) heterocycle-C₁₋₄ alkyl (preferably, 5- to8-membered heterocycle-C₁₋₄ alkyl, said 5- to 8-membered heterocycle has1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and anoptionally oxidized sulfur atom, such as imidazolyl, triazolyl and thelike), (v) optionally halogenated C₁₋₄ alkyloxy, (vi) C₁₋₄alkyl-carbonyl, (vii) cyano, (viii) carbamoyl optionally substituted byC₁₋₈ alkyl and (ix) C₁₋₄ alkoxy-carbonyl;

R^(1a) is

(i) a hydrogen atom,(ii) a cyano group, or(iii) a C₁₋₄ alkyl group or a C₂₋₄ alkenyl group, each of which isoptionally substituted by —NR⁸—CO—(CH₂)_(n)—NR⁶R⁷wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or differentand each is a hydrogen atom or a C₁₋₄ alkyl group, R⁸ is a hydrogen atomor a C₁₋₄ alkyl group, and when n is not less than 2, a subset —CH₂CH₂—of (CH₂)_(n) is optionally replaced by —CH═CH—;R^(2a) is a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group or a C₂₋₈ alkynylgroup, each of which is optionally substituted by substituent(s)selected from(a) hydroxy,(b) carboxy,(c) cyano,(d) optionally halogenated C₁₋₄ alkyloxy,(e) —O—(CH₂)_(n)—OH,(f) —O—(CH₂)_(n)—O—CO—NH₂,(g) —O—(CH₂)_(n)—O— (optionally halogenated C₁₋₄ alkyl),(h) —O—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(i) —O—(CH₂)_(n)—SO₂—C₆₋₁₈ aryl,(j) —O—(CH₂)_(n)—SO₂—(CH₂)_(n)—OH,(k) —O—(CH₂)—NR⁸—CO—C₁₋₄ alkyl,(l) —O—(CH₂)—NR⁸—CO—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(m) —O—(CH₂)_(n)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(n) —CO—NR⁸—(CH₂)_(n)—OH,(o) —CO—NR⁸—(CH₂)—SO₂— (optionally halogenated C₁₋₄ alkyl),(p) —CO—NR⁸—O—C₁₋₄ alkyl,

(q) —NR⁶R⁷,

(r) —NR⁸—(CH₂)_(n)—OH,(s) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(t) —NR⁸—CO— (optionally halogenated C₁₋₄ alkyl),(u) —NR⁸—CO—(CH₂)_(n)—OH,(v) —NR⁸—CO—(CH₂)_(n)—CN,(w) —NR⁸—CO—(CH₂)_(n)—NR⁶R⁷,(x) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(y) —NR⁸—CO—(CH₂)—SO— (optionally halogenated C₁₋₄ alkyl),(z) —NR⁸—CO—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(aa) —NR⁸—CO—(CH₂)—SO₂—C₃₋₈ cycloalkyl,(bb) —NR⁸—CO—(CH₂)_(n)—NR⁸—SO₂—C₁₋₄ alkyl,(cc) —NR⁸—CO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(dd) —NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(ee) —NR⁸—CO—NH—O—C₁₋₄ alkyl,(ff) —NR⁸—CO—NH—(CH₂)_(n)—O—C₁₋₄ alkyl,(gg) —NR⁸—C(═NH)—NH—C₁₋₄ alkyl,(hh) —NR⁸—SO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(ii) —S— (CH₂)_(n)—OH,

(jj) —SO—(CH₂)—OH,

(kk) —SO₂—(CH₂)_(n)—OH, and(ll) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—O—C₁₋₄ alkyl,—CO—NH—C₁₋₄ alkyl, —CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂and the like), wherein n is an integer of 1 to 4, R⁶ and R⁷ are the sameor different and each is a hydrogen atom or a C₁₋₄ alkyl group, R⁸ is ahydrogen atom or a C₁₋₄ alkyl group, (CH₂)_(n) is optionally substitutedby optionally halogenated C₁₋₄ alkyl or hydroxy, and when n is not lessthan 2, a subset —CH₂CH₂— of (CH₂)_(n) is optionally replaced by—CH═CH—; andR^(3a) is a hydrogen atom or a C₁₋₆ alkyl group; orR^(1a) and R^(2a) are optionally bonded to form

R^(2a) and R^(3a) are optionally bonded to form C₂₋₄ alkylene optionallysubstituted by an imino group is preferable.

As R⁸, a hydrogen atom, methyl, ethyl and the like are preferable, and ahydrogen atom is particularly preferable.

As R², a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group or a C₂₋₈ alkynyl group,each of which is optionally substituted by substituent(s) selected from

(a) hydroxy,(b) carboxy,(c) cyano,(d) optionally halogenated C₁₋₄ alkyloxy,(e) —O—(CH₂)_(n)—OH (wherein (CH₂)_(n) is optionally substituted byhydroxy),(f) —O—(CH₂)_(n)—O—CO—NH₂,(g) —O—(CH₂)—O— (optionally halogenated C₁₋₄ alkyl),(h) —O—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(i) —O—(CH₂)_(n)—SO₂—C₆₋₁₈ aryl,(j) —O—(CH₂)_(n)—SO₂—(CH₂)_(n)—OH,(k) —O—(CH₂)_(n)—NR⁸—CO—C₁₋₄ alkyl,(l) —O—(CH₂)_(n)—NR⁸—CO—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(m) —O—(CH₂)_(n)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(n) —CO—NR⁸—(CH₂)_(n)—OH,(o) —CO—NR—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(p) —CO—NR⁸—O—C₁₋₄ alkyl,

(q) —NR⁶R⁷,

(r) —NR⁸—(CH₂)_(n)—OH,(s) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(t) —NR⁸—CO— (optionally halogenated C₁₋₄ alkyl),(u) —NR⁸—CO—(CH₂)_(n)—OH (wherein (CH₂)_(n) is optionally substituted byoptionally halogenated C₁₋₄ alkyl or hydroxy),(v) —NR⁸—CO—(CH₂)_(n)—CN,(w) —NR⁸—CO—(CH₂)_(n)—NR⁶R⁷ (when n is not less than 2, a subset—CH₂CH₂— of (CH₂)_(n) is optionally replaced by —CH═CH—),(x) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(y) —NR⁸—CO—(CH₂)_(n)—SO— (optionally halogenated C₁₋₄ alkyl),(z) —NR⁸—CO—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(wherein (CH₂)_(n) is optionally substituted by C₁₋₄ alkyl),(aa) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(bb) —NR⁸—CO—(CH₂)_(n)—NR⁸—SO₂—C₁₋₄ alkyl,(cc) —NR⁸—CO₂—(CH₂)—SO₂—C₁₋₄ alkyl,(dd) —NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(ee) —NR⁸—CO—NH—O—C₁₋₄ alkyl,(ff) —NR⁸—CO—NH—(CH₂)_(n)—O—C₁₋₄ alkyl,(gg) —NR⁸—C(═NH)—NH—C₁₋₄ alkyl,(hh) —NR—SO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(ii) —S—(CH₂)_(n)—OH,(jj) —SO—(CH₂)_(n)—OH,(kk) —SO₂—(CH₂)_(n)—OH, and(ll) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—O—C₁₋₄ alkyl,—CO—NH—C₁₋₄ alkyl, —CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂and the like), wherein n is an integer of 1 to 4, R⁶ and R⁷ are the sameor different and each is a hydrogen atom or a C₁₋₄ alkyl group, and R⁸is a hydrogen atom or a C₁₋₄ alkyl group, is preferable.

As R⁸, a hydrogen atom, methyl, ethyl and the like are preferable, and ahydrogen atom is particularly preferable.

As compound (Ia), moreover, a compound wherein

B^(a) is a benzene ring optionally substituted by 1 to 4 substituentsselected from halogen and optionally halogenated C₁₋₄ alkyl;C^(a) is a phenyl group substituted by 1 to 5 substituents selected from(i) halogen, (ii) optionally halogenated C₁₋₄ alkyl, (iii) hydroxy-C₁₋₄alkyl, (iv) heterocycle-C₁₋₄ alkyl (preferably, 5- to 8-memberedheterocycle-C₁₋₄ alkyl, said 5- to 8-membered heterocycle has 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and anoptionally oxidized sulfur atom, such as imidazolyl and the like), (v)optionally halogenated C₁₋₄ alkyloxy, (vi) cyano, and (vii) carbamoyloptionally substituted by C₁₋₈ alkyl;R^(1a) is a hydrogen atom;R^(2a) is a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group or a C₂₋₈ alkynylgroup, each of which is substituted by substituent(s) selected from(a) hydroxy,(b) optionally halogenated C₁₋₄ alkyloxy,(c) —O—(CH₂)_(n)—OH,

(d) —O—(CH₂)—O—CO—NH₂,

(e) —O—(CH₂)_(n)—O—C₁₋₄ alkyl,(f) —O—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl)(g) —O—(CH₂)_(n)—SO₂—C₆₋₁₈ aryl,(h) —O—(CH₂)—SO₂—(CH₂)_(n)—OH,(i) —O—(CH₂)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl)(j) —CO—NR⁸—(CH₂)_(n)—OH,(k)—CO—NR⁸—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),

(l) —NR⁶R⁷,

(m) —NR⁸—(CH₂)_(n)—OH,(n) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(o) —NR⁸—CO—(CH₂)_(n)—OH,(p) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₁₄ alkyl,(q) —NR⁸—CO—(CH₂)_(n)—SO— (optionally halogenated C₁₋₄ alkyl),(r) —NR⁸—CO—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(s) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(t) —NR⁸—CO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(u) —NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(v) —NR⁸—SO₂—(CH₂)_(n)—SO₂—C₁₋₁₄ alkyl,(w) —S—(CH₂)_(n)—OH,

(x) —SO—(CH₂)—OH,

(y) —SO₂—(CH₂)_(n)—OH, and(z) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—NH—C₁₋₄ alkyl,—CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂ and the like),wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or differentand each is a hydrogen atom or a C₁₋₄ alkyl group, R⁸ is a hydrogen atomor a C₁₋₄ alkyl group, and (CH₂)_(n) is optionally substituted by C₁₋₄alkyl or hydroxy;R^(3a) is a hydrogen atom or a C₁₋₆ alkyl group; orR^(1a) and R^(2a) are optionally bonded to form

R^(2a) and R^(3a) are optionally bonded to form C₂₋₄ alkylene, ispreferable.

Of these, as R^(2a), a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group or a C₂₋₈alkynyl group (particularly, a C₁₋₈ alkyl group), each of which issubstituted by substituent(s) selected from (a) hydroxy,

(b) optionally halogenated C₁₋₄ alkyloxy,(c) —O—(CH₂)_(n)—OH (wherein (CH₂)_(n) is optionally substituted byhydroxy),(d) —O—(CH₂)_(n)—O—CO—NH₂,(e) —O—(CH₂)_(n)—O—C₁₋₄ alkyl,(f) —O—(CH₂)—SO₂— (optionally halogenated C₁₋₄ alkyl),(g) —O—(CH₂)_(n)—SO₂—C₆₋₁₈ aryl,(h) —O—(CH₂)_(n)—SO₂—(CH₂)_(n)—OH,(i) —O—(CH₂)_(n)—NR⁸SO₂— (optionally halogenated C₁₋₄ alkyl),(j) —CO—NRB —(CH₂)_(n)—OH,(k) —CO—NR⁸—(CH₂)—SO₂— (optionally halogenated C₁₋₄ alkyl),

(l) —NR⁶R⁷,

(m) —NR⁸—(CH₂)_(n)—OH,(n) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(o) —NR⁸—CO—(CH₂)_(n)—OH (wherein (CH₂)_(n) is optionally substituted byC₁₋₄ alkyl),(p) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(q) —NR⁸—CO—(CH₂)—SO— (optionally halogenated C₁₋₄ alkyl),(r) —NR⁸—CO—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(wherein (CH₂) is optionally substituted by C₁₋₄ alkyl),(s) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(t) —NR⁸—CO₂— (CH₂)—SO₂—C₁₋₄ alkyl,(u) —NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(v) —NR⁸—SO₂—(CH₂)—SO₂—C₁₋₄ alkyl,(w) —S— (CH₂)_(n)—OH,(x) —SO—(CH₂)_(n)—OH,

(y) —SO₂—(CH₂)—OH, and

(z) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—NH—C₁₋₄ alkyl,—CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂ and the like),wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or differentand each is a hydrogen atom or a C₁₋₄ alkyl group, R⁸ is a hydrogen atomor a C₁₋₄ alkyl group, is preferable.

As R^(2a), (i) a C₅₋₈ alkyl group substituted by hydroxy,

(ii) a C₁₋₈ alkyl group substituted by substituent(s) selected from(a) halogenated C₁₋₄ alkyloxy,(b) —O—(CH₂)_(n)—OH,(c) —O—(CH₂)_(n)—O—CO—NH₂,(d) —O—(CH₂)_(n)—O— (optionally halogenated C₁₋₄ alkyl),(e) —O—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(f) —O—(CH₂)_(n)—SO₂—C₆₋₁₈ aryl,(g) —O—(CH₂)_(n)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(h) —CO—NR⁸—(CH₂)_(n)—OH,(i) —CO—NR⁸—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(j) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(k) —NR⁸—CO—(CH₂)_(n)—OH,(l) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(m) —NR⁸—CO—(CH₂)—SO— (optionally halogenated C₁₋₄ alkyl),(n) —NR⁸—CO—(CH₂)—SO₂— (optionally halogenated C₁₋₄ alkyl),(o) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(p) —NR⁸—CO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(q) —NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(r) —NR⁸—SO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(s) —S—(CH₂)_(n)—OH,

(t) —SO—(CH₂)—OH,

(u) —SO₂—(CH₂)_(n)—OH, and(v) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—NH—C₁₋₄ alkyl,—CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂ and the like),wherein n is an integer of 1 to 4, R⁸ is a hydrogen atom or a C₁₋₄ alkylgroup, and (CH₂), is optionally substituted by C₁₋₄ alkyl or hydroxy,(iii) a C₂₋₈ alkenyl group optionally substituted by hydroxy, or(iv) a C₂₋₈ alkynyl group optionally substituted by hydroxy ispreferable, and particularly,as R^(2a), (i) a C₅₋₈ alkyl group substituted by hydroxy,(ii) a C₁₋₈ alkyl group substituted by substituent(s) selected from(a) halogenated C₁₋₄ alkyloxy,(b) —O—(CH₂)_(n)—OH (wherein (CH₂)_(n) is optionally substituted byhydroxy),(c) —O—(CH₂)_(n)—O—CO—NH₂,(d) —O—(CH₂)—O— (optionally halogenated C₁₋₄ alkyl),(e) —O—(CH₂)—SO₂— (optionally halogenated C₁₋₄ alkyl),(f) —O—(CH₂)_(n)—SO₂—C₆₋₁₈ aryl,(g) —O—(CH₂)_(n)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl)(h) —CO—NR⁸—(CH₂)_(n)—OH,(i) —CO—NR⁸—(CH₂)—SO₂— (optionally halogenated C₁₋₄ alkyl),(j) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₁₄ alkyl,(k) —NR⁸—CO—(CH₂)—OH (wherein (CH₂)_(n) is optionally substituted byC₁₋₄ alkyl),(l) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(m) —NR⁸—CO—(CH₂)_(n)—SO— (optionally halogenated C₁₋₄ alkyl),(n) —NR⁸—CO—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(wherein (CH₂)_(n) is optionally substituted by C₁₋₄ alkyl),(o) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(p) —NR⁸—CO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(q) —NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(r) —NR⁸—SO₂—(CH₂)_(n)—SO₂—C₁₋₁₄ alkyl,(s) —S— (CH₂)_(n)—OH,(t) —SO—(CH₂)_(n)—OH(u) —SO₂—(CH₂)_(n)—OH, and(v) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—NH—C₁₋₄ alkyl,—CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂ and the like),wherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group,(iii) a C₂₋₈ alkenyl group optionally substituted by hydroxy, or(iv) a C₂₋₈ alkynyl group optionally substituted by hydroxy ispreferable, and as R⁸, a hydrogen atom, methyl, ethyl and the like arepreferable, and a hydrogen atom is particularly preferable.

[Compound (Ib)]

A compound represented by the formula:

wherein R^(1b) is a hydrogen atom or an optionally substituted groupbonded via a carbon atom, a nitrogen atom or an oxygen atom,R^(2b) is an optionally substituted group bonded via a carbon atom or asulfur atom, orR^(1b) and R^(2b), or R^(2b) and R^(3b) are optionally bonded to form anoptionally substituted ring structure,R^(3b) is a hydrogen atom or an optionally substituted aliphatichydrocarbon group, or R^(3b) is optionally bonded to a carbon atom ofthe adjacent phenyl group to form an optionally substituted ringstructure,B^(b) is an optionally substituted benzene ring, C^(b) is an optionallysubstituted C₆₋₁₈ aryl group, andZ^(b) is an optionally substituted C₁₋₃ alkylene group, or a saltthereof.

As the “optionally substituted group bonded via a carbon atom, anitrogen atom or an oxygen atom” for R^(1b), those similar to the“optionally substituted group bonded via a carbon atom, a nitrogen atomor an oxygen atom” for R¹ can be used.

As the “optionally substituted group bonded via a carbon atom or asulfur atom” for R^(2b), those similar to the “optionally substitutedgroup bonded via a carbon atom or a sulfur atom” for R² can be used.

As the “optionally substituted ring structure” formed by R^(1b) andR^(2b), or R^(2b) and R^(3b) bonded to each other, those similar to the“optionally substituted ring structure” formed by R¹ and R², or R² andR³ bonded to each other can be used.

As the “optionally substituted aliphatic hydrocarbon group” for R^(3b),those similar to the “optionally substituted aliphatic hydrocarbongroup” for R³ can be used.

As the “optionally substituted ring structure” formed by R^(3b) and acarbon atom of the adjacent phenyl group, those similar to the“optionally substituted ring structure” formed by R³ and a carbon atomof the adjacent phenyl group can be used.

As the “optionally substituted benzene ring” for B^(b), those similar tothe “optionally substituted benzene ring” for B^(a) can be used.

As the “optionally substituted C₆₋₁₈ aryl group” for C^(b), thosesimilar to the “optionally substituted C₆₋₁₈ aryl group” for C^(a) canbe used.

As the “C₁₋₃ alkylene group” of the “optionally substituted C₁₋₃alkylene group” for Z^(b), methylene, ethylene, trimethylene andpropylene can be used.

As the “substituent” of the “optionally substituted C₁₋₃ alkylene group”for Z^(b), 1 to 3 substituents selected from halogen, hydroxy, C₁₋₄alkyloxy, C₁₋₄ alkyl-carbonyl, carboxy, C₁₋₄ alkoxy-carbonyl, cyano,carbamoyl, sulfamoyl, nitro, amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkoxy-carbonylamino and C₁₋₄ alkylsulfonylamino can be used.

As R^(2b), a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynylgroup, a carbamoyl group, a C₁₋₈ alkyl-carbonyl group, a C₁₋₈alkylsulfonyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₈ aryl group, aC₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈aryl-C₁₋₄ alkyl-carbonyl group, a C₆₋₁₈ aryl-sulfonyl group, aheterocyclic group, a heterocycle-C₁₋₄ alkyl group, aheterocycle-carbonyl group or a heterocycle-C₁₋₄ alkyl-carbonyl group,each of which is optionally substituted by 1 to 5 substituents selectedfrom

(a) halogen,(b) oxo,(c) optionally halogenated C₁₋₄ alkyl,(d) —(CH₂)_(m)-Q,(e) —(CH₂)_(m)-Z¹- (optionally halogenated C₁₋₄ alkyl),(f) —(CH₂)_(m)-Z¹-C₃₋₈ cycloalkyl,(g) —(CH₂)_(m)-Z²-(CH₂)_(n)-Q,(h) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹- (optionally halogenated C₁₋₄ alkyl)(i) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹-C₃₋₈ cycloalkyl,(j) —(CH₂)_(m)-Z¹- (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom),(k) —(CH₂)_(m)-Z²-C₁₋₄ alkoxy, and(l) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹-(CH₂)_(n)-Z¹-C₁₋₄ alkylwherein m is an integer of 0 to 4, n is an integer of 1 to 4,Q is hydroxy, carboxy, cyano, nitro, —NR⁶R⁷, —CONR⁶R⁷, —OCONH₂ or—SO₂NR⁶R⁷,Z¹ is —O—, —CO—, —C(OH)R⁸—, —C(═N—OR⁸)—, —S—, —O—, —SO₂—, —N(COR⁸)—,—N(CO₂R⁹)—, —N(SO₂R⁸)—, —CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—, —NR⁸—CO₂—,—NR⁸—CO—NH—, —NR⁸—SO₂—, or —NR⁸—C(═NH)—NH—,Z² is —O—, —CO—, —C(OH)R⁸—, —C(═N—OR⁸)—, —S—, —SO—, —SO₂—, —NR⁸—,—N(COR⁸)—, —N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁸—NR⁸—CO—,—NR⁸—CO₂—, —NR⁸—CO—NH—, —NR⁸—C(═NH)—NH—, —NR⁸—SO₂—, or —SO₂—NR⁸—,(CH₂)_(m) and (CH₂), are optionally substituted by 1 to 5 substituentsselected from halogen, optionally halogenated C₁₋₄ alkyl and hydroxy,and when m or n is not less than 2, a subset —CH₂CH₂— of (CH₂)_(m) and(CH₂)_(n), is optionally replaced by —CH═CH— or —C≡C—,R⁶ and R⁷ are the same or different and each is a hydrogen atom or aC₁₋₄ alkyl group, or R⁶ and R⁷ are bonded to form, together with anitrogen atom, a 3- to 8-membered saturated or unsaturated aliphaticheterocyclic group,R⁸ is a hydrogen atom or C₁₋₄ alkyl, and R⁹ is C₁₋₄ alkyl is preferable.

As compound (Ib), a compound wherein

B^(b) is a benzene ring optionally substituted by halogen;C^(b) is a phenyl group optionally substituted by 1 to 5 substituentsselected from halogen, optionally halogenated C₁₋₄ alkyl and cyano;R^(1b) is (i) a hydrogen atom, or(ii) a C₂₋₄ alkenyl group optionally substituted by hydroxy;

R^(2b) is

(i) a C₁₋₈ alkyl group optionally substituted by substituent(s) selectedfrom(a) halogen,(b) hydroxy,(c) C₁₋₄ alkyloxy,(d) —O—(CH₂)_(n)—OH,(e) —O—(CH₂)_(n)—O—C₁₋₄ alkyl,(f) —CO—NR⁸—(CH₂)_(n)—OH,

(g) —NR⁶R⁷ and (h) —NR⁸—(CH₂)—OH,

wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or differentand each is a hydrogen atom or a C₁₋₄ alkyl group, and R⁸ is a hydrogenatom or a C₁₋₄ alkyl group,(ii) a C₆₋₁₈ aryl-C₁₋₄ alkyl group optionally substituted bysubstituent(s) selected from(a) C₁₋₄ alkyl optionally having hydroxy,(b) carboxy,(c) C₁₋₄ alkoxy-carbonyl,(d) 5- to 8-membered heterocycle-carbonyl having 1 to 3 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom, whichoptionally has substituent(s) selected from hydroxy and C₁₋₄ alkyl, and(e) C₁₋₄ alkyl-carbamoyl optionally having substituent(s) selected fromhydroxy and carbamoyl,(iii) a C₆₋₁₈ aryl-carbonyl group optionally substituted by C₁₋₄ alkoxy,(iv) a C₆₋₁₈ aryl-sulfonyl group optionally substituted by C₁₋₄ alkoxy,or(v) a 5- to 8-membered heterocycle-C₁₋₄ alkyl group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,which is optionally substituted by substituent(s) selected from(a) carboxy, and(b) C₁₋₄ alkoxy-carbonyl;R^(3b) is a hydrogen atom or a C₁₋₆ alkyl group; orR^(2b) and R^(3b) are optionally bonded to form C₂₋₄ alkylene; andZ^(b) is a C₁₋₃ alkylene group is preferable.

Moreover, as compound (Ib), a compound wherein

B^(b) is a benzene ring optionally substituted by halogen;C^(b) is a phenyl group optionally substituted by 1 to 5 substituentsselected from halogen and optionally halogenated C₁₋₄ alkyl;R^(1b) is a hydrogen atom;R^(2b) is a C₁₋₈ alkyl group optionally substituted by substituent(s)selected from(a) hydroxy,(b) —O—(CH₂)_(n)—OH,(c) —O—(CH₂)_(n)—O—C₁₋₄ alkyl,(d) —CO—NR⁸—(CH₂)_(n)—OH,

(e) —NR⁶R⁷, and

(f) —NR⁸—(CH₂)_(n)—OH,wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or differentand each is a hydrogen atom or a C₁₋₄ alkyl group, and R⁸ is a hydrogenatom or a C₁₋₄ alkyl group;R^(3b) is a hydrogen atom or a C₁₋₆ alkyl group; andZ^(b) is a C₁₋₃ alkylene group is preferable.

Particularly, as compound (Ib), a compound wherein

B^(b) is a benzene ring optionally substituted by halogen;C^(b) is a phenyl group optionally substituted by 1 to 5 substituentsselected from halogen and optionally halogenated C₁₋₄ alkyl;R^(1b) is a hydrogen atom;R^(2b) is a C₁₋₈ alkyl group substituted by substituent(s) selected from(a) —O—(CH₂)_(n)—OH,(b) —O—(CH₂)_(n)—O—C₁₋₄ alkyl, and(c) —CO—NR⁸—(CH₂)_(n)—OH,wherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group;R^(3b) is a hydrogen atom or a C₁₋₆ alkyl group; andZ^(b) is a methylene group is preferable.

As R⁸, a hydrogen atom, methyl, ethyl and the like are preferable, and ahydrogen atom is particularly preferable.

[Compound (Ic)]

A compound represented by the formula:

wherein R¹⁰ is a hydrogen atom or an optionally substituted group bondedvia a carbon atom, a nitrogen atom or an oxygen atom,R^(2c) is an optionally substituted group bonded via a carbon atom or asulfur atom, orR^(1c) and R^(2c), or R^(2c) and R^(3c) are optionally bonded to form anoptionally substituted ring structure,R^(3c) is a hydrogen atom or an optionally substituted aliphatichydrocarbon group, or R^(3c) is optionally bonded to a carbon atom ofthe adjacent phenyl group to form an optionally substituted ringstructure,B^(c) is an optionally substituted benzene ring, and cc is an optionallysubstituted heterocyclic group, or a salt thereof.

As the “optionally substituted group bonded via a carbon atom, anitrogen atom or an oxygen atom” for R¹⁰, those similar to the“optionally substituted group bonded via a carbon atom, a nitrogen atomor an oxygen atom” for R¹ can be used.

As the “optionally substituted group bonded via a carbon atom or asulfur atom” for R^(2c), those similar to the “optionally substitutedgroup bonded via a carbon atom or a sulfur atom” for R² can be used.

As the “optionally substituted ring structure” formed by R^(1c) andR^(2c), or R^(2c) and R^(3c) bonded to each other, those similar to the“optionally substituted ring structure” formed by R¹ and R², or R² andR³ bonded to each other can be used.

As the “optionally substituted aliphatic hydrocarbon group” for R^(3c),those similar to the “optionally substituted aliphatic hydrocarbongroup” for R³ can be used.

As the “optionally substituted ring structure” formed by R^(3c) and acarbon atom of the adjacent phenyl group, those similar to the“optionally substituted ring structure” formed by R³ and a carbon atomof the adjacent phenyl group can be used.

As the “optionally substituted benzene ring” for BC, those similar tothe “optionally substituted benzene ring” for B^(a) can be used.

As the “heterocyclic group” of the “optionally substituted heterocyclicgroup” for C^(c), the aforementioned “heterocyclic group” can be used,and a 5- to 8-membered heterocyclic group having 1 to 3 hetero atomsselected from a nitrogen atom, an oxygen atom and an optionally oxidizedsulfur atom can be particularly preferably used. Specifically, 5 or6-membered aromatic monocyclic heterocyclic groups such as furyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, 3-to 8-membered (preferably 5- or 6-membered) saturated or unsaturated(preferably saturated) aliphatic heterocyclic groups such as oxiranyl,azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl,thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl,piperazinyl, dihydro-1,2,4-oxadiazolyl and the like can be used, andparticularly, pyridyl, pyrimidinyl, piperidyl (particularly,4-piperidyl) and the like are preferable.

As the “substituent” of the “optionally substituted heterocyclic group”for C^(c), those similar to the “substituent” of the “optionallysubstituted C₆₋₁₈ aryl group” for C^(a) can be used.

As R², a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynyl group, acarbamoyl group, a C₁₋₈ alkyl-carbonyl group, a C₁₋₈ alkylsulfonylgroup, a C₃₋₈ cycloalkyl group, a C₆₋₁₈ aryl group, a C₆₋₁₈ aryl-C₁₋₄alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈ aryl-C₁₋₄alkyl-carbonyl group, a C₆₋₁₈ aryl-sulfonyl group, a heterocyclic group,a heterocycle-C₁₋₄ alkyl group, a heterocycle-carbonyl group or aheterocycle-C₁₋₄ alkyl-carbonyl group, each of which is optionallysubstituted by 1 to 5 substituents selected from

(a) halogen,(b) oxo,(c) optionally halogenated C₁₋₄ alkyl,(d) —(CH₂)_(m)-Q,(e) —(CH₂)_(m)-Z¹- (optionally halogenated C₁₋₄ alkyl),(f) —(CH₂)_(m)-Z¹-C₃₋₈ cycloalkyl,(g) —(CH₂)_(m)-Z²-(CH₂)_(n)-Q,(h) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹- (optionally halogenated C₁₋₄ alkyl),(i) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹-C₃₋₈ cycloalkyl,(j) —(CH₂)_(m)-Z¹- (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom),(k) —(CH₂)_(m)-Z²-C₁₋₄ alkoxy, and(l) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹-(CH₂)_(n)-Z¹-C₁₋₄ alkylwherein m is an integer of 0 to 4, n is an integer of 1 to 4,Q is hydroxy, carboxy, cyano, nitro, —NR⁶R⁷, —CONR⁶R⁷ or —SO₂NR⁶R⁷,Z¹ is —O—, —CO—, —C(OH)R⁸—, —C(═N—OR⁸)—, —S—, —SO—, —SO₂—, —N(COR⁸)—,—N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—, —NR⁸—CO₂—,—NR⁸—CO—NH—, —NR⁸—SO₂—, or —NR⁸—C(═NH)—NH—,Z² is —O—, —CO—, —C(OH)R⁸—, —C(═N—OR⁸)—, —S—, —SO, SO₂—, —NR⁸—,—N(COR⁸)—, —N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—,—NR⁸—CO₂—, —NR⁸—CO—NH—, —NR⁸—C(═NH)—NH—, —NR⁸—SO₂—, or —SO₂—NR⁸—,(CH₂)_(m) and (CH₂), are optionally substituted by 1 to 5 substituentsselected from halogen, optionally halogenated C₁₋₄ alkyl and hydroxy,and when m or n is not less than 2, a subset —CH₂CH₂— of (CH₂)_(m) and(CH₂)— is optionally replaced by —CH═CH—,R⁶ and R⁷ are the same or different and each is a hydrogen atom or aC₁₋₄ alkyl group, or R⁶ and R⁷ are bonded to form, together with anitrogen atom, a 3- to 8-membered saturated or unsaturated aliphaticheterocyclic group,R⁸ is a hydrogen atom or C₁₋₄ alkyl, and R⁹ is C₁₋₄ alkyl is preferable.

As compound (Ic), a compound wherein

B^(c) is a benzene ring optionally substituted by 1 to 4 substituentsselected from halogen and optionally halogenated C₁₋₄ alkyl;C^(c) is a 5- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom(e.g., pyridyl, pyrimidyl, 4-piperidyl), which is optionally substitutedby 1 to 5 substituents selected from(i) halogen,(ii) C₁₋₄ alkyl,(iii) C₁₋₄ alkyl-carbonyl,(iv) optionally halogenated C₁₋₄ alkoxy-carbonyl,(v) C₃₋₈ cycloalkyl-carbonyl, and(vi) a carbamoyl group optionally substituted by substituent(s) selectedfrom(a) optionally halogenated C₁₋₈ alkyl,(b) C₃₋₈ cycloalkyl, and(c) C₆₋₁₈ aryl optionally substituted by substituent(s) selected fromhalogen, C₁₋₄ alkyl and C₁₋₄ alkyloxy;R^(1c) is (i) a hydrogen atom,(ii) a C₂₋₄ alkenyl group optionally substituted by hydroxy, or(iii) a 5- to 8-membered heterocyclic group having 1 to 3 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom;

R^(2c) is

(i) a C₁₋₄ alkyl group optionally substituted by substituent(s) selectedfrom(a) halogen,(b) hydroxy,(c) C₁₋₄ alkyloxy,(d) carboxy,(e) C₁₋₄ alkoxy-carbonyl,(f) —O—(CH₂)_(n)—OH,(g) —O—(CH₂)—O—C₁₋₄ alkyl,(h) —CO—NR⁸—(CH₂)_(n)—OH, and(i) —NR⁸—CO—(CH₂)_(n)—SO₂—C₁₋₄ alkylwherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group, or(ii) a C₆₋₁₈ aryl-C₁₋₄ alkyl group optionally substituted by C₁₋₄ alkyloptionally having hydroxy; andR^(3c) is a hydrogen atom or a C₁₋₆ alkyl group; orR^(2c) and R^(3c) are optionally bonded to form C₂₋₄ alkylene ispreferable.

Moreover, as compound (Ic), a compound wherein

B^(c) is a benzene ring optionally substituted by 1 to 4 substituentsselected from halogen and C₁₋₄ alkyl;C^(c) is a 5- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,which is optionally substituted by 1 to 5 substituents selected from(i) C₁₋₄ alkyl,(ii) C₁₋₄ alkyl-carbonyl,(iii) optionally halogenated C₁₋₄ alkoxy-carbonyl,(iv) C₃₋₈ cycloalkyl-carbonyl, and(v) a carbamoyl group optionally substituted by substituent(s) selectedfrom(a) optionally halogenated C₁₋₈ alkyl,(b) C₃₋₈ cycloalkyl, and(c) C₆₋₁₈ aryl optionally substituted by halogen;R^(1c) is a hydrogen atom;R^(2c) is a C₁₋₄ alkyl group optionally substituted by substituent(s)selected from(a) hydroxy,(b) C₁₋₄ alkyloxy,(c) —O—(CH₂)_(n)—OH,(d) —O—(CH₂)_(n)—O—C₁₋₄ alkyl, and(e) —NR⁸—CO(CH₂)_(n)—SO₂—C₁₋₄ alkylwherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group; andR^(3c) is a hydrogen atom or a C₁₋₆ alkyl group is preferable,particularly, a compound wherein R^(2c) is a C₁₋₄ alkyl group optionallysubstituted by substituent(s) selected from(a) —O—(CH₂)_(n)—OH, and(b) —O—(CH₂)_(n)—O—C₁₋₄ alkyl, wherein n is an integer of 1 to 4 ispreferable.

[Compound (Id)]

A compound represented by the formula

wherein R^(1d) is a hydrogen atom or an optionally substituted groupbonded via a carbon atom, a nitrogen atom or an oxygen atom,R^(2d) is an optionally substituted group bonded via a carbon atom or asulfur atom, orR^(1d) and R^(2d), or R^(2d) and R^(3d) are optionally bonded to form anoptionally substituted ring structure,R^(3d) is a hydrogen atom or an optionally substituted aliphatichydrocarbon group, or R^(3d) is optionally bonded to a carbon atom ofthe adjacent phenyl group to form an optionally substituted ringstructure,B^(d) is an optionally substituted benzene ring, C^(d) is an optionallysubstituted heterocyclic group, andZ^(d) is an optionally substituted C₁₋₃ alkylene group, or a saltthereof.

As the “optionally substituted group bonded via a carbon atom, anitrogen atom or an oxygen atom” for R^(1d), those similar to the“optionally substituted group bonded via a carbon atom, a nitrogen atomor an oxygen atom” for R¹ can be used.

As the “optionally substituted group bonded via a carbon atom or asulfur atom” for R^(2d), those similar to the “optionally substitutedgroup bonded via a carbon atom or a sulfur atom” for R² can be used.

As the “optionally substituted ring structure” formed by R^(1d) andR^(2d), or R^(2d) and R^(3d) bonded to each other, those similar to the“optionally substituted ring structure” formed by R¹ and R², or R² andR³ bonded to each other can be used.

As the “optionally substituted aliphatic hydrocarbon group” for R^(3d),those similar to the “optionally substituted aliphatic hydrocarbongroup” for R³ can be used.

As the “optionally substituted ring structure” formed by R^(3d) and acarbon atom of the adjacent phenyl group, those similar to the“optionally substituted ring structure” formed by R³ and a carbon atomof the adjacent phenyl group can be used.

As the “optionally substituted benzene ring” for B^(d), those similar tothe “optionally substituted benzene ring” for B^(a) can be used.

As the “optionally substituted heterocyclic group” for C^(d), thosesimilar to the “optionally substituted heterocyclic group” for C^(c) canbe used.

As the “optionally substituted C₁₋₃ alkylene group” for Z^(d), thosesimilar to the “optionally substituted C₁₋₃ alkylene group” for Z^(b)can be used.

As R^(2d), a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynylgroup, a carbamoyl group, a C₁₋₈ alkyl-carbonyl group, a C₁₋₈alkylsulfonyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₈ aryl group, aC₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈aryl-C₁₋₄ alkyl-carbonyl group, a C₆₋₁₈ aryl-sulfonyl group, aheterocyclic group, a heterocycle-C₁₋₄ alkyl group, aheterocycle-carbonyl group or a heterocycle-C₁₋₄ alkyl-carbonyl group,each of which is optionally substituted by 1 to 5 substituents selectedfrom

(a) halogen,(b) oxo,(c) optionally halogenated C₁₋₄ alkyl,(d) —(CH₂)_(m)-Q,(e) —(CH₂)_(m)-Z¹- (optionally halogenated C₁₋₄ alkyl),(f) —(CH₂)_(f-Z) ¹-C₃₋₈ cycloalkyl,(g) —(CH₂)_(m)-Z²-(CH₂)_(n)-Q,(h) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z²-(optionally halogenated C₂₋₄ alkyl),(i) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z-C₃₋₈ cycloalkyl,(j) —(CH₂)_(m)-Z¹- (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom),(k) —(CH₂)_(m)-Z²-C₁₋₄ alkoxy, and(l) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹-(CH₂)_(n)-Z¹-C₁₋₄ alkylwherein m is an integer of 0 to 4, n is an integer of 1 to 4, Q ishydroxy, carboxy, cyano, nitro, —NR⁶R⁷, —CONR⁶R⁷ or —SO₂NR⁶R⁷,Z¹ is —O—, —CO—, —C(OH)R⁸—, —C(═N—OR⁸)—, —S—, —SO—, —SO₂—, —N(COR⁸)—,—N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—, —NR⁸—CO₂—,—NR⁸—CO—NH—, —NR⁸SO₂—, or —NR⁸—C(═NH)—NH—,Z² is —O—, —CO—, —C(OH)R⁵—, —C(═N—OR⁸)—, —S—, —SO—, —SO₂—, —NR⁸—,—N(COR⁸)—, —N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—,—NR⁸—CO₂—, —NR⁸—CO—NH—, —NR⁸—C(═NH)—NH—, —NR⁸—SO₂—, or —SO₂—NR⁸—,(CH₂)_(m) and (CH₂)_(n) are optionally substituted by 1 to 5substituents selected from halogen, optionally halogenated C₁₋₄ alkyland hydroxy, and when m or n is not less than 2, a subset —CH₂CH₂— of(CH₂)_(m) and (CH₂)_(n) is optionally replaced by —CH═CH—,R⁶ and R⁷ are the same or different and each is a hydrogen atom, or aC₁₋₄ alkyl group, or R⁶ and R⁷ are bonded to form, together with anitrogen atom, a 3- to 8-membered saturated or unsaturated aliphaticheterocyclic group,R⁸ is a hydrogen atom or C₁₋₄ alkyl, and R⁹ is C₁₋₄ alkyl, ispreferable.

As compound (Id), a compound wherein

B^(d) is a benzene ring optionally substituted by halogen;C^(d) is a 5- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;R^(1d) is a hydrogen atom;

R^(2d) is

(i) C₁₋₄ alkyl optionally substituted by substituent(s) selected from(a) C₁₋₄ alkyloxy(b) —O—(CH₂)_(n)—OH, and(c) —NR⁸—CO—(CH₂)_(n)—SO₂—C₁₋₄ alkylwherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group, or(ii) a 5- to 8-membered heterocycle-C₁₋₄ alkyl group having 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfuratom, which is optionally substituted by substituent(s) selected from(a) carboxy, and(b) C₁₋₄ alkoxy-carbonyl;R^(3d) is a hydrogen atom or a C₁₋₆ alkyl group; andZ^(d) is a C₁₋₃ alkylene group is preferable.

Moreover, as compound (Id), a compound wherein

B^(d) is a benzene ring optionally substituted by halogen;C^(d) is a 5- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;R^(1d) is a hydrogen atom,R^(2d) is a C₁₋₄ alkyl group optionally substituted by C₁₋₄ alkyloxy,R^(3d) is a hydrogen atom or a C₁₋₆ alkyl group; andZ^(d) is a methylene group is preferable.

[Compound (Ie)]

A compound represented by the formula:

wherein R^(2e) is an optionally substituted group bonded via a carbonatom or a sulfur atom, orR^(2e) and R^(3e) are optionally bonded to form an optionallysubstituted ring structure,R^(3e) is a hydrogen atom or an optionally substituted aliphatichydrocarbon group, or R^(3e) is optionally bonded to a carbon atom ofthe adjacent phenyl group to form an optionally substituted ringstructure,B^(e) is an optionally substituted benzene ring, and C^(e) is anoptionally substituted C₆₋₁₈ aryl group, or a salt thereof.

As the “optionally substituted group bonded via a carbon atom or asulfur atom” for R^(2e), those similar to the “optionally substitutedgroup bonded via a carbon atom or a sulfur atom” for R² can be used.

As the “optionally substituted ring structure” formed by R^(2e) andR^(3e) bonded to each other, those similar to the “optionallysubstituted ring structure” formed by R² and R³ bonded to each other canbe used.

As the “optionally substituted aliphatic hydrocarbon group” for R^(3e),those similar to the “optionally substituted aliphatic hydrocarbongroup” for R³ can be used.

As the “optionally substituted ring structure” formed by R^(3e) and acarbon atom of the adjacent phenyl group, those similar to the“optionally substituted ring structure” formed by R³ and a carbon atomof the adjacent phenyl group can be used.

As the “optionally substituted benzene ring” for B^(e), those similar tothe “optionally substituted benzene ring” for B^(a) can be used.

As the “optionally substituted C₆₋₁₈ aryl group” for C^(e), thosesimilar to the “optionally substituted C₆₋₁₈ aryl group” for C^(a) canbe used.

As R^(2e), a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynylgroup, a carbamoyl group, a C₁₋₁₈ alkyl-carbonyl group, a C₁₋₈alkylsulfonyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₈ aryl group, aC₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈aryl-C₁₋₄ alkyl-carbonyl group, a C₆₋₁₈ aryl-sulfonyl group, aheterocyclic group, a heterocycle-C₁₋₄ alkyl group, aheterocycle-carbonyl group or a heterocycle-C₁₋₄ alkyl-carbonyl group,each of which is optionally substituted by 1 to 5 substituents selectedfrom

(a) halogen,(b) oxo,(c) optionally halogenated C₁₋₄ alkyl,(d) —(CH₂)_(m)-Q,(e) —(CH₂)_(m)-Z¹- (optionally halogenated C₁₋₄ alkyl),(f) —(CH₂)_(m)-Z¹-C₃₋₈ cycloalkyl,(g) —(CH₂)_(m)-Z²-(CH₂)_(n)-Q,(h) —(CH₂)-Z²-(CH₂)_(n)-Z¹-optionally halogenated C₁₋₄ alkyl,(i) —(CH₂)_(m)-Z —(CH₂)_(n)-Z¹-C₃₋₈ cycloalkyl,(j) —(CH₂)_(m)-Z¹- (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom),(k) (CH₂)_(m)-Z²-C₁₋₄ alkoxy, and(l) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹-(CH₂)_(n)-Z¹-C₁₋₄ alkyl wherein m is aninteger of 0 to 4, n is an integer of 1 to 4, Q is hydroxy, carboxy,cyano, nitro, —NR⁶R⁷, —CONR⁶R⁷ or —SO₂NR⁶R⁷,Z¹ is —O—, —CO—, —C(OH)R⁸—, —C(═N—OR⁸)—, —S—, —SO—, —SO₂—, —N(COR⁸)—,—N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁸—NR⁸—CO—, —NR⁸—CO₂—,—NR⁸—CO—NH—, —NR⁸SO₂—, or —NR⁸—C(═NH)—NH—,Z² is —O—, —CO—, —C(OH)R⁸—, —C(═N—OR⁸)—, —S—, —SO—, —SO₂—, —NR⁸—,—N(COR⁸)—, —N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—,—NR⁸—CO₂—, —NR⁸—CO—NH—, —NR⁸—C(═NH)—NH—, —NR⁸SO₂—, or —SO₂—NR⁸—,(CH₂)_(m) and (CH₂)_(n) are optionally substituted by 1 to 5substituents selected from halogen, optionally halogenated C₁₋₄ alkyland hydroxy, and when m or n is not less than 2, a subset —CH₂CH₂— of(CH₂)_(m) and (CH₂)_(n) is optionally substituted by —CH═CH—,R⁶ and R⁷ are the same or different and each is a hydrogen atom, or aC₁₋₄ alkyl group, or R⁶ and R⁷ are bonded to form, together with anitrogen atom, a 3- to 8-membered saturated or unsaturated aliphaticheterocyclic group,R⁸ is a hydrogen atom or C₁₋₄ alkyl, and R⁹ is C₁₋₄ alkyl is preferable.

As compound (Ie), a compound wherein

B^(e) is a benzene ring optionally substituted by halogen;C^(e) is a phenyl group optionally substituted by optionally halogenatedC₁₋₄ alkyl; andR^(2e) is a C₁₋₄ alkyl group optionally substituted by —O—(CH₂)_(n)—OHwherein n is an integer of 1 to 4 is preferable.

Moreover, as compound (Ie), a compound wherein

B^(e) is a benzene ring optionally substituted by halogen;C^(e) is a phenyl group optionally substituted by optionally halogenatedC₁₋₄ alkyl; andR^(2e) is a C₁₋₄ alkyl group substituted by —O—(CH₂)_(n)—OH wherein n isan integer of 1 to 4 is preferable.

[Compound (If)]

A compound represented by the formula:

wherein R^(2f) is an optionally substituted group bonded via a carbonatom or a sulfur atom, orR^(2f) and R^(3f) are optionally bonded to form an optionallysubstituted ring structure,R^(3f) is a hydrogen atom or an optionally substituted aliphatichydrocarbon group, or R^(3f) is optionally bonded to a carbon atom ofthe adjacent phenyl group to form an optionally substituted ringstructure,B^(f) is an optionally substituted benzene ring, C^(f) is an optionallysubstituted C₆₋₁₈ aryl group, andZ^(f) is an optionally substituted C₁₋₃ alkylene group, or a saltthereof.

As the “optionally substituted group bonded via a carbon atom or asulfur atom” for R², those similar to the “optionally substituted groupbonded via a carbon atom or a sulfur atom” for R² can be used.

As the “optionally substituted ring structure” formed by R^(2f) andR^(3f) bonded to each other, those similar to the “optionallysubstituted ring structure” formed by R² and R³ bonded to each other canbe used.

As the “optionally substituted aliphatic hydrocarbon group” for R³,those similar to the “optionally substituted aliphatic hydrocarbongroup” for R³ can be used.

As the “optionally substituted ring structure” formed by R^(3f) and acarbon atom of the adjacent phenyl group, those similar to the“optionally substituted ring structure” formed by R³ and a carbon atomof the adjacent phenyl group can be used.

As the “optionally substituted benzene ring” for B^(f), those similar tothe “optionally substituted benzene ring” for B^(a) can be used.

As the “optionally substituted C₆₋₁₈ aryl group” for C^(f), thosesimilar to the “optionally substituted C₆₋₁₈ aryl group” for C^(a) canbe used.

As the “optionally substituted C₁₋₃ alkylene group” for Z^(f), thosesimilar to the “optionally substituted C₁₋₃ alkylene group” for Z^(b)can be used.

As R^(2f), a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynylgroup, a carbamoyl group, a C₁₋₈ alkyl-carbonyl group, a C₁₋₈alkylsulfonyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₈ aryl group, aC₆₋₁₈ aryl-C₁₋₁₄ alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈aryl-C₁₋₄ alkyl-carbonyl group, a C₆₋₁₈ aryl-sulfonyl group, aheterocyclic group, a heterocycle-C₁₋₄ alkyl group, aheterocycle-carbonyl group or a heterocycle-C₁₋₄ alkyl-carbonyl group,each of which is optionally substituted by 1 to 5 substituents selectedfrom

(a) halogen,(b) oxo,(c) optionally halogenated C₁₋₄ alkyl,(d) —(CH₂)_(m)-Q,(e) —(CH₂)_(m)-Z¹- (optionally halogenated C₁₋₄ alkyl),(f) —(CH₂)_(m)-Z¹-C₃₋₈ cycloalkyl,(g) —(CH₂)_(m)-Z²-(CH₂)_(n)-Q,(h) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z- optionally halogenated C₁₋₄ alkyl,(i) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹-C₃₋₈ cycloalkyl,(j) —(CH₂)_(m)-Z¹- (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom),(k) —(CH₂)_(m)-Z²-C₁₋₄ alkoxy, and(l) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹-(CH₂)_(n)-Z¹-C₁₋₄ alkylwherein m is an integer of 0 to 4, n is an integer of 1 to 4, Q ishydroxy, carboxy, cyano, nitro, —NR⁶R⁷, —CONR⁶R⁷ or —SO₂NR⁶R⁷,Z¹ is —O—, —CO—, —C(OH)R⁸—, —C(═N—OR⁸)—, —S—, —SO—, —SO₂—, —N(COR⁸)—,—N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁶—, —NR⁸—CO—, —NR⁸—CO₂—,—NR⁸—CO—NH—, —NR⁸SO₂—, or —NR⁸—C(═NH)—NH—,Z² is —O— —CO—, —C(OH)R⁸—, —C((═N—OR⁸)—, —S—, —SO—, —SO₂—, —NR⁸—,—N(COR⁸)—, —N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—,—NR⁸—CO₂—, —NR⁸—CO—NH—, —NR⁸—C(═NH)—NH—, —NR⁸—SO₂— or —SO₂—NR⁸—,(CH₂)_(m) and (CH₂)_(n) are optionally substituted by 1 to 5substituents selected from halogen, optionally halogenated C₁₋₄ alkyland hydroxy, and when m or n is not less than 2, a subset —CH₂CH₂— of(CH₂)_(m) and (CH₂)_(n) is optionally substituted by —CH═CH—,R⁶ and R⁷ are the same or different and each is a hydrogen atom, or aC₁₋₄ alkyl group, or R⁶ and R⁷ are bonded to form, together with anitrogen atom, a 3- to 8-membered saturated or unsaturated aliphaticheterocyclic group,R⁸ is a hydrogen atom or C₁₋₄ alkyl, and R⁹ is C₁₋₄ alkyl, ispreferable.

As compound (If), a compound wherein

B^(f) is a benzene ring optionally substituted by halogen;C^(f) is a phenyl group optionally substituted by halogen;

R^(2f) is

(i) a C₁₋₄ alkyl group optionally substituted by 1 to 5 substituentsselected from the group consisting of(a) hydroxy,(b) —O—(CH₂)_(n)—OH,(c) —NR⁸—(CH₂)_(n)—O—C₁₋₄ alkyl,(d) —NR⁸—(CH₂)_(n)-heterocyclic group (preferably, said heterocyclicgroup is a 5- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom),and(e) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,wherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group,(ii) a C₆₋₁₈ aryl group optionally substituted by 1 to 5 substituentsselected from the group consisting of (a) C₁₋₄ alkyl optionallysubstituted by substituent(s) selected from hydroxy, —NR⁸—(CH₂)_(n)—OH,—NR⁸—(CH₂)_(n)—O—C₁₋₄ alkyl, —NR⁸—(CH₂)_(n)-heterocyclic group(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and a sulfur atom) and —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl, and(b) —CO—NR⁸—(CH₂)_(n)—O—C₁₋₄ alkyl,wherein n is an integer of 1 to 4, and R^(e) is a hydrogen atom or aC₁₋₄ alkyl group, or(iii) a C₆₋₁₈ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5substituents selected from the group consisting of(a) carboxy,(b) C₁₋₄ alkoxy-carbonyl, and(c) —CO—NR⁸—(CH₂)_(n)—O—C₁₋₄ alkyl,wherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group,R^(3f) is a hydrogen atom or a C₁₋₆ alkyl group; andZ^(f) is a C₁₋₃ alkylene group; orR^(2f) and R^(3f) are optionally bonded to form C₂₋₄ alkylene ispreferable.

As R^(e), a hydrogen atom, methyl, ethyl and the like are preferably,and a hydrogen atom is particularly preferable.

Moreover, as compound (If), a compound wherein

B^(f) is a benzene ring optionally substituted by halogen;C^(f) is a phenyl group optionally substituted by halogen;R^(2f) is a C₁₋₄ alkyl group optionally substituted by 1 to 5substituents selected from the group consisting of(a) hydroxy, and(b) —O—(CH₂)_(n)—OH wherein n is an integer of 1 to 4;R^(3f) is a hydrogen atom or a C₁₋₆ alkyl group;Z^(f) is methylene is preferable, and particularly, a compound whereinR^(2f) is a C₁₋₄ alkyl group substituted by —O—(CH₂)_(n)—OH wherein n isan integer of 1 to 4 is preferable.

[Compound (Ig)]

A compound represented by the formula:

wherein R^(2g) is an optionally substituted group bonded via a carbonatom or a sulfur atom, orR^(2g) and R^(3g) are optionally bonded to form an optionallysubstituted ring structure,R^(3g) is a hydrogen atom or an optionally substituted aliphatichydrocarbon group, or R^(3g) is optionally bonded to a carbon atom ofthe adjacent phenyl group to form an optionally substituted ringstructure,B^(g) is an optionally substituted benzene ring, and C^(g) is anoptionally substituted heterocyclic group, or a salt thereof.

As the “optionally substituted group bonded via a carbon atom or asulfur atom” for R²⁹, those similar to the “optionally substituted groupbonded via a carbon atom or a sulfur atom” for R² can be used.

As the “optionally substituted ring structure” formed by R²⁹ and R³⁹bonded to each other, those similar to the “optionally substituted ringstructure” formed by R² and R³ bonded to each other can be used.

As the “optionally substituted aliphatic hydrocarbon group” for R^(3g),those similar to the “optionally substituted aliphatic hydrocarbongroup” for R³ can be used.

As the “optionally substituted ring structure” formed by R^(3g) and acarbon atom of the adjacent phenyl group, those similar to the“optionally substituted ring structure” formed by R³ and a carbon atomof the adjacent phenyl group can be used.

As the “optionally substituted benzene ring” for B^(g), those similar tothe “optionally substituted benzene ring” for B^(a) can be used.

As the “optionally substituted heterocyclic group” for C^(g), thosesimilar to the “optionally substituted heterocyclic group” for C^(c) canbe used.

As R^(2g), a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynylgroup, a carbamoyl group, a C₁₋₈ alkyl-carbonyl group, a C₁₋₈alkylsulfonyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₈ aryl group, aC₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈aryl-C₁₋₄ alkyl-carbonyl group, a C₆₋₁₈ aryl-sulfonyl group, aheterocyclic group, a heterocycle-C₁₋₄ alkyl group, aheterocycle-carbonyl group or a heterocycle-C₁₋₄ alkyl-carbonyl group,each of which is optionally substituted by 1 to 5 substituents selectedfrom

(a) halogen,(b) oxo,(c) optionally halogenated C₁₋₄ alkyl,(d) —(CH₂)_(m)-Q,(e) —(CH₂)_(m)-Z¹- (optionally halogenated C₁₋₄ alkyl),(f) —(CH₂)_(m)-Z¹-C₃₋₈ cycloalkyl,(g) —(CH₂)_(m)-Z²-(CH₂)_(n)-Q,(h) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹- (optionally halogenated C₁₋₄ alkyl),(i) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹-C₃₋₈ cycloalkyl,(j) —(CH₂)_(m)-Z¹- (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom),(k) —(CH₂)_(m)-Z²-C₁₋₄ alkoxy, and(l) —(CH₂)_(m)-Z²-(CH₂)_(n)-Z¹-(CH₂)_(n)-Z¹-C₁₋₄ alkylwherein m is an integer of 0 to 4, n is an integer of 1 to 4, Q ishydroxy, carboxy, cyano, nitro, —NR⁶R⁷, —CONR⁶R⁷ or —SO₂NR⁶R⁷,Z¹ is —O—, —CO—, —C(OH)R⁸—, —C(═N—OR⁸)—, —S—, —SO—, —SO₂—, —N(COR⁸)—,—N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—, —NR⁸—CO₂—,—NR⁸—CO—NH—, —NR⁸—SO₂—, or —NR⁸—C(═NH)—NH—,Z² is —O—, —CO—, —C(OH)R⁸—, —C(═N—OR⁸)—, —S—, —SO—, —SO₂—, —NR⁸—,—N(COR⁸)—, —N(CO₂R⁹)—, —N(SO₂R⁹)—, —CO—O—, —O—CO—, —CO—NR⁸—, —NR⁸—CO—,—NR⁸—CO₂—, —NR⁸—CO—NH—, —NR⁸—C(═NH)—NH—, —NR⁸—SO₂—, or —SO₂—NR⁸—,(CH₂)_(m) and (CH₂)_(n) are optionally substituted by 1 to 5substituents selected from halogen, optionally halogenated C₁₋₄ alkyland hydroxy, and when m or n is not less than 2, a subset —CH₂CH₂— of(CH₂)_(m) and (CH₂)_(n) is optionally replaced by —CH═CH—.R⁶ and R⁷ are the same or different and each is a hydrogen atom, or aC₁₋₄ alkyl group, or R⁶ and R⁷ are bonded to form, together with anitrogen atom, a 3- to 8-membered saturated or unsaturated aliphaticheterocyclic group,R⁸ is a hydrogen atom or C₁₋₄ alkyl, and R⁹ is C₁₋₄ alkyl, ispreferable.

As compound (Ig), a compound wherein

B^(g) is a benzene ring optionally substituted by C₁₋₄ alkyl;C^(g) is a 5- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,which is optionally substituted by C₁₋₄ alkyl

R^(2g) is

(i) a C₁₋₄ alkyl group optionally substituted by hydroxy,(ii) a C₆₋₁₈ aryl group optionally substituted by substituent(s)selected from(a) nitro,(b) amino,(c) —CO—NR⁸—(CH₂)_(n)—O—C₁₋₄ alkyl,(d) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,

(e) —NR⁸CO—(CH₂)—NR⁶R⁷,

(f) —NR⁸—CO—(CH₂)_(n)—COOH,(g) —NR⁸CO(CH₂)_(n)—CO₂—C₁₋₄ alkyl, and(h) —NR⁸—CO—(CH₂)_(m)—O —(CH₂)_(n)—O—C₁₋₄ alkyl,wherein m is an integer of 0 to 4, n is an integer of 1 to 4,R⁶ and R⁷ are the same or different and each is a hydrogen atom or aC₁₋₄ alkyl group, and R⁸ is a hydrogen atom or a C₁₋₄ alkyl group, or(iii) a C₆₋₁₈ aryl-C₁₋₄ alkyl group optionally substituted bysubstituent(s) selected from(a) carboxy,(b) C₁₋₄ alkoxy-carbonyl, and(c) —CO—NR⁸—(CH₂)_(n)—O—C₁₋₄ alkyl,wherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group;R^(3g) is a hydrogen atom or a C₁₋₆ alkyl group; orR^(2g) and R^(3g) are optionally bonded to form C₂₋₄ alkylene ispreferable.

As compound (Ig), a compound wherein

R^(2g) is

(i) a C₆₋₁₈ aryl group optionally substituted by substituent(s) selectedfrom(a) nitro,(b) amino,(c) —CO—NR⁸—(CH₂)—O—C₁₋₄ alkyl,(d) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(e) —NR⁸—CO—(CH₂)_(n)—NR⁶R⁷,(f) —NR⁸—CO—(CH₂)_(n)—COOH,(g) —NR⁸—CO—(CH₂)_(n)—CO₂—C₁₋₄ alkyl, and(h) —NR⁸—CO—(CH₂)_(m)—O —(CH₂)_(n)—O—C₁₋₄ alkyl,wherein m is an integer of 0 to 4, n is an integer of 1 to 4,R⁶ and R⁷ are the same or different and each is a hydrogen atom or aC₁₋₄ alkyl group, and R⁸ is a hydrogen atom or a C₁₋₄ alkyl group, or(ii) a C₆₋₁₈ aryl-C₁₋₄ alkyl group substituted by substituent(s)selected from(a) carboxy,(b) C₁₋₄ alkoxy-carbonyl, and(c) —CO—NR⁸—(CH₂)—O—C₁₋₄ alkyl,wherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group, is preferable.

As R⁸, a hydrogen atom, methyl, ethyl and the like are preferable, and ahydrogen atom is particularly preferable.

[Compound (Ih)]

A compound (I) selected from the following (A) to (H).

(A) A compound (I) wherein W is CR¹;A is a phenyloxy-C₆₋₁₈ aryl group wherein the phenyloxy moiety isoptionally substituted by 1 to 5 substituents selected from(i) halogen,(ii) optionally halogenated C₁₋₄ alkyl,(iii) hydroxy-C₁₋₄ alkyl,(iv) heterocycle-C₁₋₄ alkyl (preferably, 5- to 8-memberedheterocycle-C₁₋₄ alkyl, said 5- to 8-membered heterocycle has 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and anoptionally oxidized sulfur atom, such as imidazolyl, triazolyl and thelike),(v) optionally halogenated C₁₋₄ alkyloxy,(vi) C₁₋₄ alkyl-carbonyl,(vii) cyano,(viii) carbamoyl optionally substituted by C₁₋₈ alkyl, and(ix) C₁₋₄ alkoxy-carbonyl, and the C₆₋₁₈ aryl moiety is optionallyfurther substituted by 1 to 4 substituents selected from halogen, C₁₋₄alkyl, hydroxy-C₁₋₄ alkyl, C₁₋₄ alkyloxy, carboxy and C₁₋₄alkoxy-carbonyl;X¹ is —NR^(3′)— wherein R^(3′) is a hydrogen atom or a C₁₋₆ alkyl group;

R¹ is

(i) a hydrogen atom,(ii) a cyano group, or(iii) a C₁₋₄ alkyl group or a C₂₋₄ alkenyl group, each of which isoptionally substituted by —NR⁸—CO—(CH₂)_(n)—NR⁶R⁷wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or differentand each is a hydrogen atom or a C₁₋₄ alkyl group, R⁸ is a hydrogen atomor a C₁₋₄ alkyl group, and when n is not less than 2, a subset —CH₂CH₂—of (CH₂)_(n) is optionally replaced by —CH═CH—;R² is (i) a hydrogen atom or(ii) a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group or a C₂₋₈ alkynyl group,each of which is optionally substituted by substituent(s) selected from(a) hydroxy,(b) carboxy,(c) cyano,(d) optionally halogenated C₁₋₄ alkyloxy,(e) —O—(CH₂)_(n)—OH,(f) —O—(CH₂)_(n)—O—CO—NH₂,(g) —O—(CH₂)—O— (optionally halogenated C₁₋₄ alkyl),(h) —O—(CH₂)—SO₂— (optionally halogenated C₁₋₄ alkyl),(i) —O—(CH₂)_(n)—SO₂—C₆₋₁₈ aryl,(j) —O—(CH₂)_(n)—SO₂—(CH₂)_(n)—OH,(k) —O—(CH₂)—NR⁸—CO—C₁₋₄ alkyl,(l) —O—(CH₂)_(n)—NR⁸—CO—(CH₂)—SO₂—C₁₋₄ alkyl,(m) —O—(CH₂)_(n)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(n) —CO—NR⁸ (CH₂)_(n)—OH,(o) —CO—NR⁸—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl), (p)—CO—NR⁸—O—C₁₋₄ alkyl,

(q) —NR⁶R⁷,

(r) —NR⁸—(CH₂)_(n)—OH,(s) —NR⁸—(CH₂)—SO₂—C₁₋₄ alkyl,(t) —NR⁸—CO— (optionally halogenated C₁₋₄ alkyl),(u) —NR⁸—CO—(CH₂)_(n)—OH,(v) —NR⁸—CO—(CH₂)_(n)—CN,(w) —NR⁸—CO—(CH₂)_(n)—NR⁶R⁷,(x) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(y) —NR⁸—CO—(CH₂)_(n)—SO— (optionally halogenated C₁₋₄ alkyl),(z) —NR⁸—CO—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(aa) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(bb) —NR⁸—CO—(CH₂)_(n)—NR⁸—SO₂—C₁₋₄ alkyl,(cc) —NR⁸—CO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(dd) —NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(ee) —NR⁸—CO—NH—O—C₁₋₄ alkyl,(ff) —NR⁸—CO—NH—(CH₂)_(n)—O—C₁₋₄ alkyl,(gg) —NR⁸—C(═NH)—NH—C₁₋₄ alkyl,(hh) —NR⁸—SO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(ii) —S— (CH₂)_(n)—OH,(jj) —SO—(CH₂)_(n)—OH,(kk) —SO₂—(CH₂)_(n)—OH, and(ll) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—O—C₁₋₄ alkyl,—CO—NH—C₁₋₄ alkyl, —CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂and the like)wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or differentand each is a hydrogen atom or a C₁₋₄ alkyl group, R⁸ is a hydrogen atomor a C₁₋₄ alkyl group, (CH₂)_(n) is optionally substituted by optionallyhalogenated C₁₋₄ alkyl or hydroxy, and when n is not less than 2, and asubset —CH₂CH₂— of (CH₂)_(n) is optionally replaced by —CH═CH—; orR¹ and R² are optionally bonded to form

R² and R^(3′) are optionally bonded to form C₂₋₄ alkylene optionallysubstituted by an imino group, particularly preferably, R^(2a) is a C₁₋₈alkyl group, a C₂₋₈ alkenyl group or a C₂₋₈ alkynyl group (particularly,C₁₋₈ alkyl group), each of which is optionally substituted bysubstituent(s) selected from

(a) hydroxy,(b) carboxy,(c) cyano,(d) optionally halogenated C₁₋₄ alkyloxy,(e) —O—(CH₂)_(n)—OH (wherein (CH₂)_(n) is optionally substituted byhydroxy),(f) —O—(CH₂)_(n)—O—CO—NH₂,(g) —O—(CH₂)_(n)—O— (optionally halogenated C₁₋₄ alkyl),(h) —O—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(i) —O—(CH₂)_(n)—SO₂—C₆-18 aryl,(j) —O—(CH₂)_(n)—SO₂—(CH₂)_(n)—OH,(k) —O—(CH₂)_(n)—NR⁸—CO—C₁₋₄ alkyl,(l) —O—(CH₂)—NR⁸—CO—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(m) —O—(CH₂)_(n)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(n) —CO—NR⁸—(CH₂)_(n)—OH,(o) —CO—NR⁸—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(p) —CO—NR⁸—O—C₁₋₄ alkyl,

(q) —NR⁶R⁷,

(r) —NR⁸—(CH₂)_(n)—OH,(s) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(t) —NR⁸—CO— (optionally halogenated C₁₋₄ alkyl),(u) —NR⁸—CO—(CH₂)_(n)—OH (wherein (CH₂)_(n) is optionally substituted byoptionally halogenated C₁₋₄ alkyl or hydroxy),(v) —NR⁸—CO—(CH₂)_(n)—CN,(w) —NR⁸CO—(CH₂)_(n)—NR⁶R⁷ (when n is not less than 2, a subset —CH₂CH₂—of (CH₂)_(n) is optionally replaced by —CH═CH—),(x) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(y) —NR⁸CO—(CH₂)_(n)—SO— (optionally halogenated C₁₋₄ alkyl),(z) —NR⁸—CO—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(wherein (CH₂)_(n) is optionally substituted by C₁₋₄ alkyl),(aa) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(bb) —NR⁸—CO—(CH₂)_(n)—NR⁸—SO₂—C₁₋₄ alkyl,(cc) —NR⁸—CO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(dd) —NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(ee) —NR⁸—CO—NH—O—C₁₋₄ alkyl,(ff) —NR⁸—CO—NH—(CH₂)_(n)—O—C₁₋₄ alkyl,(gg) —NR⁸—C(═NH)—NH—C₁₋₄ alkyl,(hh) —NR⁸—SO₂—(CH₂)—SO₂—C₁₋₄ alkyl,(ii) —S— (CH₂)_(n)—OH,

(jj) —SO—(CH₂)—OH,

(kk) —SO₂—(CH₂)_(n)—OH, and(ll) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—O—C₁₋₄ alkyl,—CO—NH—C₁₋₄ alkyl, —CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂and the like)wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or differentand each is a hydrogen atom or a C₁₋₄ alkyl group, and R⁸ is a hydrogenatom or a C₁₋₄ alkyl group.(B) A compound (I) wherein W is CR¹;A is a phenyl-C₁₋₃ alkyloxy-C₆₋₁₈ aryl group wherein the phenyl moietyis optionally substituted by 1 to 5 substituents selected from halogen,optionally halogenated C₁₋₄ alkyl and cyano, andthe C₆₋₁₈ aryl moiety is optionally further substituted by 1 to 4substituents selected from halogen, C₁₋₄ alkyl optionally having hydroxyand C₁₋₄ alkyloxy;X¹ is —NR^(3′) wherein R^(3′) is a hydrogen atom or a C₁₋₆ alkyl group;R¹ is (i) a hydrogen atom, or(ii) a C₁₋₄ alkyl group or a C₂₋₄ alkenyl group, each of which isoptionally substituted by substituent(s) selected from(a) hydroxy,(b) amino, and

(c) —NR⁸—CO—(CH₂)—NR⁶R⁷,

wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or differentand each is a hydrogen atom or a C₁₋₄ alkyl group, and R⁸ is a hydrogenatom or a C₁₋₄ alkyl group,(iii) a C₆₋₁₈ aryl group optionally substituted by substituent(s)selected from(a) amino,(b) carboxy,(c) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl, and(d) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl, wherein n is an integer of 1 to 4,and R⁸ is a hydrogen atom or a C₁₋₄ alkyl group, and when n is not lessthan 2, a subset —CH₂—CH₂ of (CH₂)_(n) is optionally replaced by—CH═CH—, or(iv) a 5- to 8-membered heterocyclic group having 1 to 3 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom;R² is (i) a hydrogen atom,(ii) a C₁₋₈ alkyl group optionally substituted by substituent(s)selected from(a) halogen,(b) hydroxy,(c) C₁₋₄ alkyloxy,(d) —O—(CH₂)_(n)—OH,(e) —O—(CH₂)_(n)—O—C₁₋₄ alkyl,(f) —CO—NR⁸—(CH₂)_(n)—OH,

(g) —NR⁶R⁷, and

(h) —NR⁸—(CH₂)_(n)—OH,wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or differentand each is a hydrogen atom or a C₁₋₄ alkyl group, and R⁸ is a hydrogenatom or a C₁₋₄ alkyl group,(iii) a C₆₋₁₈ aryl-C₁₋₄ alkyl group optionally substituted bysubstituent(s) selected from (a) C₁₋₄ alkyl optionally having hydroxy,(b) carboxy,(c) C₁₋₄ alkoxy-carbonyl,(d) 5- to 8-membered heterocycle-carbonyl having 1 to 3 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom, whichoptionally has substituent(s) selected from hydroxy and C₁₋₄ alkyl, and(e) C₁₋₄ alkyl-carbamoyl optionally having substituent(s) selected fromhydroxy and carbamoyl,(iv) a C₆₋₁₈ aryl-carbonyl group optionally substituted by C₁₋₄ alkoxy,(v) a C₆₋₁₈ aryl-sulfonyl group optionally substituted by C₁₋₄ alkoxy,or(vi) a 5- to 8-membered heterocycle-C₁₋₄ alkyl group having 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfuratom, which is optionally substituted by substituent(s) selected from(a) carboxy, and(b) C₁₋₄ alkoxy-carbonyl; orR² and R³— are optionally bonded to form C₂₋₄ alkylene.(C) A compound (I) wherein W is CR¹;A is a 5- to 8-membered heterocycleoxy-C₆₋₁₈ aryl group containing 1 to3 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom, wherein the heterocycleoxy moiety is optionally substitutedby 1 to 5 substituents selected from(i) halogen,(ii) C₁₋₄ alkyl,(iii) C₁₋₄ alkyl-carbonyl,(iv) optionally halogenated C₁₋₄ alkoxy-carbonyl,(v) C₃₋₈ cycloalkyl-carbonyl, and(vi) a carbamoyl group optionally substituted by substituent(s) selectedfrom(a) optionally halogenated C₁₋₈ alkyl,(b) C₃₋₈ cycloalkyl, and(c) C₆₋₁₈ aryl optionally substituted by substituent(s) selected fromhalogen, C₁₋₄ alkyl and C₁₋₄ alkyloxy, and the C₆₋₁₈ aryl moiety isoptionally further substituted by 1 to 4 substituents selected fromhalogen and optionally halogenated C₁₋₄ alkyl;

X¹ is —NR^(3′)— wherein R^(3′) is a hydrogen atom or a C₁₋₆ alkyl group;

R¹ is (i) a hydrogen atom,(ii) a C₁₋₄ alkyl group or a C₂₋₄ alkenyl group, each of which isoptionally substituted by substituent(s) selected from(a) hydroxy,(b) amino,

(c) —NR⁸—CO— (CH₂)—NR⁶R⁷, and

(d) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or differentand each is a hydrogen atom or a C₁₋₄ alkyl group, R⁸ is a hydrogen atomor a C₁₋₄ alkyl group, and when n is not less than 2, a subset —CH₂CH₂—of (CH₂), is optionally replaced by —CH═CH—,(iii) a C₆₋₁₈ aryl group optionally substituted by substituent(s)selected from(a) C₁₋₄ alkyl optionally substituted by substituent(s) selected fromhydroxy, —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl and —NR⁸—CO—(CH₂)—O—C₁₋₄ alkyl,(b) amino,(c) C₁₋₄ alkyloxy,(d) carboxy, and(e) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,wherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group, or(iv) a 5- to 8-membered heterocyclic group having 1 to 3 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom;R² is (i) a hydrogen atom,(ii) a C₁₋₄ alkyl group optionally substituted by substituent(s)selected from(a) halogen,(b) hydroxy,(c) C₁₋₄ alkyloxy,(d) carboxy,(e) C₁₋₄ alkoxy-carbonyl,

(f) —O—(CH₂)—OH,

(g) —O—(CH₂)_(n)—O—C₁₋₄ alkyl,

(h) —CO—NR⁸—(CH₂)—OH, and

(i) —NR⁸—CO—(CH₂)_(n)—SO₂—C₁₋₄ alkylwherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group, or(iii) a C₆₋₁₈ aryl-C₁₋₄ alkyl group optionally substituted by C₁₋₄ alkyloptionally having hydroxy; orR² and R^(3′) are optionally bonded to form C₂₋₄ alkylene.(D) A compound (I) wherein W is CR¹;A is 5- to 8-membered heterocycle-C₁₋₃ alkyloxy-C₆₋₁₈ aryl groupcontaining 1 to 3 hetero atoms selected from a nitrogen atom, an oxygenatom and a sulfur atom;wherein the C₆₋₁₈ aryl moiety is optionally further substituted byhalogen;X¹ is —NR^(3′)— wherein R^(3′) is a hydrogen atom or a C₁₋₆ alkyl group;R¹ is (i) a hydrogen atom or(ii) a 5- to 8-membered heterocyclic group having 1 to 3 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom;R² is (i) a hydrogen atom,(ii) C₁₋₄ alkyl optionally substituted by substituent(s) selected from(a) C₁₋₄ alkyloxy,(b) —O—(CH₂)_(n)—OH, and(c) —NR⁸—CO—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,wherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group, or(iii) a 5- to 8-membered heterocycle-C₁₋₄ alkyl group having 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfuratom, which is optionally substituted by substituent(s) selected from(a) carboxy, and(b) C₁₋₄ alkoxy-carbonyl.(E) A compound (I) wherein W is N;A is a phenyloxy-C₆₋₁₈ aryl group wherein the phenyloxy moiety isoptionally substituted by 1 to 5 substituents selected from optionallyhalogenated C₁₋₄ alkyl and cyano, and the C₆₋₁₈ aryl moiety isoptionally further substituted by 1 to 4 substituents selected fromhalogen and C₁₋₄ alkyl;X¹ is —NR^(3′) wherein R^(3′) is a hydrogen atom or a C₁₋₆ alkyl group;R² is (i) a hydrogen atom or(ii) a C₁₋₄ alkyl group optionally substituted by —O—(CH₂)_(n)—OHwherein n is an integer of 1 to 4.(F) A compound (I) wherein W is N;A is a phenyl-C₁₋₃ alkyloxy-C₆₋₁₈ aryl group wherein the phenyl moietyis optionally substituted by 1 to 5 substituents selected from halogenand cyano, and the C₆₋₁₈ aryl moiety is optionally further substitutedby 1 to 5 substituents selected from halogen and C₁₋₄ alkyl;X¹ is —NR^(3′)— wherein R^(3′) is a hydrogen atom or a C₁₋₆ alkyl group;R² is (i) a hydrogen atom,(ii) a C₁₋₄ alkyl group optionally substituted by 1 to 5 substituentsselected from the group consisting of(a) hydroxy,(b) —O—(CH₂)_(n)—OH,(c) —NR⁸—(CH₂)_(n)—O—C₁₋₄ alkyl,(d) —NR⁸—(CH₂)_(n)-heterocyclic group (preferably, said heterocyclicgroup is a 5- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom),and(e) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,wherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group,(iii) a C₆₋₁₈ aryl group optionally substituted by C₁₋₄ alkyl optionallysubstituted by substituent(s) selected from hydroxy, —NR⁸—(CH₂)_(n)—OH,—NR⁸—(CH₂)_(n)-heterocyclic group (preferably, said heterocyclic groupis a 5- to 8-membered heterocyclic group having 1 to 3 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom) and—NR⁸—(CH₂)—SO₂—C₁₋₄ alkyl, or(iv) a C₆₋₁₈ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5substituents selected from the group consisting of(a) carboxy,(b) C₁₋₄ alkoxy-carbonyl, and(c) —CO—NR⁸—(CH₂)_(n)—O—C₁₋₄ alkyl,wherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group; orR² and R³ are optionally bonded to form C₂₋₄ alkylene.(G) A compound (I) wherein W is N;A is a 5- to 8-membered heterocycleoxy-C₆₋₁₈ aryl group containing 1 to3 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom, wherein the heterocycleoxy moiety is optionally substitutedby C₁₋₄ alkyl, and the C₆₋₁₈ aryl moiety is optionally furthersubstituted by C₁₋₄ alkyl;X¹ is —NR^(3′)— wherein R^(3′) is a hydrogen atom or a C₁₋₆ alkyl group;R² is (i) a hydrogen atom,(ii) a C₁₋₄ alkyl group optionally substituted by hydroxy,(iii) a C₆₋₁₈ aryl group optionally substituted by substituent(s)selected from(a) nitro,(b) amino,(c) —CO—NR⁸—(CH₂)_(n)—O—C₁₋₄ alkyl,(d) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(e) —NR⁸—CO—(CH₂)_(n)—NR⁶R⁷,(f) —NR⁸—CO—(CH₂)_(n)—COOH,(g) —NR⁸—CO—(CH₂)—CO₂—C₁₋₄ alkyl, and(h) —NR⁸—CO—(CH₂)_(m)—O—(CH₂)_(n)—O—C₁₋₄ alkyl,wherein m is an integer of 0 to 4, n is an integer of 1 to 4, R⁶ and R⁷are the same or different and each is a hydrogen atom or a C₁₋₄ alkylgroup, and R⁸ is a hydrogen atom or a C₁₋₄ alkyl group, or(iv) a C₆₋₁₉ aryl-C₁₋₄ alkyl group optionally substituted bysubstituent(s) selected from(a) carboxy,(b) C₁₋₄ alkoxy-carbonyl, and(c) —CO—NR⁸—(CH₂)_(n)—O—C₁₋₄ alkyl,wherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₋₄alkyl group; andR² and R^(3′) are optionally bonded to form C₂₋₄ alkylene.(H) A compound (I) wherein W is CH;A is a C₆₋₁₈ aryl group optionally substituted by substituent(s)selected from(a) carboxy,(b) C₁₋₄ alkoxy-carbonyl,(c) a 5- to 8-membered heterocycle-carbonyl group containing 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfuratom (preferably, a 5- to 8-membered cyclic amino-carbonyl groupoptionally having 1 or 2 hetero atoms selected from a nitrogen atom, anoxygen atom and a sulfur atom), which is optionally substituted by C₆₋₁₈aryl-C₁₋₄ alkyl,(d) a carbamoyl group optionally substituted by C₆₋₁₈ aryl-C₁₋₄ alkyl,and(e) a ureido group optionally substituted by C₆₋₁₈ aryl-C₁₋₄ alkyl;X¹ is —NR^(3′)— wherein R³ is a hydrogen atom or a C₁₋₆ alkyl group; andR² is a hydrogen atom.

[Compound (Ii)]

A compound (I) wherein A is a C₆₋₁₈ aryl group substituted bysubstituent(s) selected from

(i) a phenyloxy group substituted by 1 to 5 substituents selected from(a) halogen,(b) optionally halogenated C₁₋₄ alkyl,(c) hydroxy-C₁₋₄ alkyl,(d) heterocycle-C₁₋₄ alkyl (preferably, 5- to 8-memberedheterocycle-C₁₋₄ alkyl, said 5- to 8-membered heterocycle has 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and anoptionally oxidized sulfur atom, such as imidazolyl, triazolyl and thelike),(e) optionally halogenated C₁₋₄ alkyloxy,(f) C₁₋₄ alkyl-carbonyl,(g) cyano,(h) carbamoyl optionally substituted by C₁₋₈ alkyl, and(i) C₁₋₄ alkoxy-carbonyl,(ii) a phenyl-C₁₋₃ alkyloxy group substituted by 1 to 5 substituentsselected from(a) halogen,(b) optionally halogenated C₁₋₄ alkyl,(c) hydroxy-C₁₋₄ alkyl,(d) heterocycle-C₁₋₄ alkyl (preferably, 5- to 8-memberedheterocycle-C₁₋₄ alkyl, said 5- to 8-membered heterocycle has 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and anoptionally oxidized sulfur atom, such as imidazolyl, triazolyl and thelike),(e) optionally halogenated C₁₋₄ alkyloxy,(f) C₁₋₄ alkyl-carbonyl,(g) cyano,(h) carbamoyl optionally substituted by C₁₋₈ alkyl, and(i) C₁₋₄ alkoxy-carbonyl,(iii) a 5- to 8-membered heterocycleoxy group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,which is substituted by 1 to 5 substituents selected from(a) halogen,(b) optionally halogenated C₁₋₄ alkyl,(c) hydroxy-C₁₋₄ alkyl,(d) heterocycle-C₁₋₄ alkyl (preferably, 5- to 8-memberedheterocycle-C₁₋₄ alkyl, said 5- to 8-membered heterocycle has 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and anoptionally oxidized sulfur atom, such as imidazolyl, triazolyl and thelike),(e) optionally halogenated C₁₋₄ alkyloxy,(f) C₁₋₄ alkyl-carbonyl,(g) cyano,(h) carbamoyl optionally substituted by C₁₋₈ alkyl, and(i) C₁₋₄ alkoxy-carbonyl, and(iv) 5- to 8-membered heterocycle-C₁₋₃ alkyloxy containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,which is substituted by 1 to 5 substituents selected from(a) halogen,(b) optionally halogenated C₁₋₄ alkyl,(c) hydroxy-C₁₋₄ alkyl,(d) heterocycle-C₁₋₄ alkyl (preferably, 5- to 8-memberedheterocycle-C₁₋₄ alkyl, said 5- to 8-membered heterocycle has 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and anoptionally oxidized sulfur atom, such as imidazolyl, triazolyl and thelike),(e) optionally halogenated C₁₋₄ alkyloxy,(f) C₁₋₄ alkyl-carbonyl,(g) cyano,(h) carbamoyl optionally substituted by C₁₋₈ alkyl, and(i) C₁₋₄ alkoxy-carbonyl;wherein the C₆₋₁₈ aryl group is optionally further substituted by 1 to 4substituents selected from halogen and optionally halogenated C₁₋₄alkyl;R¹ is a hydrogen atom;R² is a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group or a C₂₋₈ alkynyl group,each of which is substituted by substituent(s) selected from(a) hydroxy,(b) carboxy,(c) cyano,(d) optionally halogenated C₁₋₄ alkyloxy,(e) —O—(CH₂)_(n)—OH,(f) —O—(CH₂)_(n)—O—CO—NH₂,(g) —O—(CH₂)_(n)—O— (optionally halogenated C₁₋₄ alkyl),(h) —O—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(i) —O—(CH₂)_(n)—SO₂—C₆₋₁₈ aryl,(j) —O—(CH₂)_(n)—SO₂—(CH₂)_(n)—OH,(k) —O—(CH₂)_(n)—NR⁸—CO—C₁₋₄ alkyl,(l) —O—(CH₂)_(n)—NR⁸—CO—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(m) —O—(CH₂)_(n)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(n) —CO—NR⁸—(CH₂)_(n)—OH,(o) —CO—NR⁸—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(p) —CO—NR⁸—O—C₁₋₄ alkyl,

(q) —NR⁶R⁷,

(r) —NR⁸—(CH₂)_(n)—OH,(s) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(t) —NR⁸—CO— (optionally halogenated C₁₋₄ alkyl),(u) —NR⁸—CO—(CH₂)_(n)—OH,(v) —NR⁸—CO—(CH₂)_(n)—CN,(w) —NR⁸—CO—(CH₂)_(n), —NR⁶R⁷,(x) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(y) —NR⁸—CO—(CH₂)_(n)—SO— (optionally halogenated C₁₋₄ alkyl),(z) —NR⁸—CO—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(aa) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(bb) —NR⁸—CO—(CH₂)_(n)—NR⁸—SO₂—C₁₋₄ alkyl,(cc) —NR⁸—CO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(dd) —NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(ee) —NR⁸—CO—NH—O—C₁₋₄ alkyl,(ff) —NR⁸—CO—NH—(CH₂)_(n)—O—C₁₋₄ alkyl,(gg) —NR⁸—C(═NH)—NH—C₁₋₄ alkyl,(hh) —NR⁸—SO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(ii) —S—(CH₂)_(n)—OH,(jj) —SO—(CH₂)_(n)—OH,(kk) —SO₂—(CH₂)_(n)—OH, and(ll) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—O—C₁₋₄ alkyl,—CO—NH—C₁₋₄ alkyl, —CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂and the like),wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or differentand each is a hydrogen atom or a C₁₋₄ alkyl group, R⁸ is a hydrogen atomor a C₁₋₄ alkyl group,(CH₂)_(n) is optionally substituted by optionally halogenated C₁₋₄ alkylor hydroxy, and when n is not less than 2, a subset —CH₂CH₂— of(CH₂)_(n) is optionally replaced by —CH═CH—;R³ is a hydrogen atom or a C₁₋₆ alkyl group; orR¹ and R² are optionally bonded to form

R² and R³ are optionally bonded to form C₂₋₄ alkylene optionallysubstituted by an imino group,particularly preferably, R² is a C₁₋₈ alkyl group, a C₂₋₈ alkenyl groupor a C₂₋₈ alkynyl group (particularly, C₁₋₈ alkyl group), each of whichis optionally substituted by substituent(s) selected from(a) hydroxy,(b) carboxy,(c) cyano,(d) optionally halogenated C₁₋₄ alkyloxy,(e) —O—(CH₂)_(n)—OH (wherein (CH₂) n is optionally substituted byhydroxy),(f) —O—(CH₂)_(n)—O—CO—NH₂,(g) —O—(CH₂)—O— (optionally halogenated C₁₋₄ alkyl),(h) —O—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(i) —O—(CH₂)—SO₂—C₆₋₁₈ aryl,(j) —O—(CH₂)—SO₂—(CH₂)_(n)—OH,(k) —O—(CH₂)—NR⁸—CO—C₁₋₄ alkyl,(l) —O—(CH₂)_(n)—NR⁸—CO—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(m) —O—(CH₂)_(n)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(n) —CO—NR⁸—(CH₂)_(n)—OH,(o) —CO—NR⁸—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(p) —CO—NR⁸—O—C₁₋₄ alkyl,

(q) —NR⁶R⁷,

(r) —NR⁸—(CH₂)_(n)—OH,(s) —NR⁸—(CH₂)—SO₂—C₁₋₄ alkyl,(t) —NR⁸—CO— (optionally halogenated C₁₋₄ alkyl),(u) —NR⁸—CO—(CH₂)_(n)—OH (wherein (CH₂)_(n) is optionally substituted byoptionally halogenated C₁₋₄ alkyl or hydroxy),(v) —NR⁸—CO—(CH₂)_(n)—CN,(w) —NR⁸—CO—(CH₂)_(n)—NR⁶R⁷ (when n is not less than 2, a subset—CH₂CH₂— of (CH₂)_(n) is optionally replaced by —CH═CH—),(x) —NR⁸CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(y) —NR⁸—CO—(CH₂)—SO— (optionally halogenated C₁₋₄ alkyl),(z) —NR⁸—CO—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl)(wherein (CH₂) is optionally substituted by C₁₋₄ alkyl),(aa) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(bb) —NR⁸—CO—(CH₂)_(n)—NR⁸—SO₂—C₁₋₄ alkyl,(cc) —NR⁸—CO₂—(CH₂)—SO₂—C₁₋₁₄ alkyl,(dd) —NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(ee) —NR⁸—CO—NH—O—C₁₋₄ alkyl,(ff) —NR⁸—CO—NH—(CH₂)_(n)—O—C₁₋₄ alkyl,(gg) —NR⁸—C(═NH)—NH—C₁₋₄ alkyl,(hh) —NR⁸—SO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(ii) —S— (CH₂)_(n)—OH,

(jj) —SO—(CH₂)—OH,

(kk) —SO₂—(CH₂)_(n)—OH, and(ll) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—O—C₁₋₄ alkyl,—CO—NH—C₁₋₄ alkyl, —CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂and the like), wherein n is an integer of 1 to 4, R⁶ and R⁷ are the sameor different and each is a hydrogen atom or a C₁₋₄ alkyl group, and R⁸is a hydrogen atom or a C₁₋₄ alkyl group.

[Compound (Ij)]

A compound (I) wherein

A is a C₆₋₁₈ aryl group substituted by substituent(s) selected from(i) a phenyloxy group substituted by 1 to 5 substituents selected from(a) halogen,(b) optionally halogenated C₁₋₄ alkyl,(c) hydroxy-C₁₋₄ alkyl,(d) heterocycle-C₁₋₄ alkyl (preferably, 5- to 8-memberedheterocycle-C₁₋₄ alkyl, said 5- to 8-membered heterocycle has 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and anoptionally oxidized sulfur atom, such as imidazolyl and the like),(e) optionally halogenated C₁₋₄ alkyloxy,(f) cyano,(g) carbamoyl optionally substituted by C₁₋₈ alkyl, and(h) C₁₋₄ alkoxy-carbonyl,(ii) a phenyl-C₁₋₃ alkyloxy group substituted by 1 to 5 substituentsselected from(a) halogen,(b) optionally halogenated C₁₋₄ alkyl,(c) hydroxy-C₁₋₄ alkyl,(d) heterocycle-C₁₋₄ alkyl (preferably, 5- to 8-memberedheterocycle-C₁₋₄ alkyl, said 5- to 8-membered heterocycle has 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and anoptionally oxidized sulfur atom, such as imidazolyl and the like),(e) optionally halogenated C₁₋₄ alkyloxy,(f) cyano,(g) carbamoyl optionally substituted by C₁₋₈ alkyl, and(h) C₁₋₄ alkoxy-carbonyl,(iii) a 5- to 8-membered heterocycleoxy group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,which is substituted by 1 to 5 substituents selected from(a) halogen,(b) optionally halogenated C₁₋₄ alkyl,(c) hydroxy-C₁₋₄ alkyl,(d) heterocycle-C₁₋₄ alkyl (preferably, 5- to 8-memberedheterocycle-C₁₋₄ alkyl, said 5- to 8-membered heterocycle has 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and anoptionally oxidized sulfur atom, such as imidazolyl and the like),(e) optionally halogenated C₁₋₄ alkyloxy,(f) cyano,(g) carbamoyl optionally substituted by C₁₋₈ alkyl, and(h) C₁₋₄ alkoxy-carbonyl, and(iv) 5- to 8-membered heterocycle-C₁₋₃ alkyloxy containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,which is substituted by 1 to 5 substituents selected from(a) halogen,(b) optionally halogenated C₁₋₄ alkyl,(c) hydroxy-C₁₋₄ alkyl,(d) heterocycle-C₁₋₄ alkyl (preferably, 5- to 8-memberedheterocycle-C₁₋₄ alkyl having 1 to 3 hetero atoms selected from anitrogen atom, an oxygen atom and an optionally oxidized sulfur atom,such as imidazolyl and the like),(e) optionally halogenated C₁₋₄ alkyloxy,(f) cyano,(g) carbamoyl optionally substituted by C₁₋₈ alkyl, and(h) C₁₋₄ alkoxy-carbonyl;wherein the C₆₋₁₈ aryl group is optionally further substituted by 1 to 4substituents selected from halogen and optionally halogenated C₁₋₄alkyl;R¹ is a hydrogen atom;R² is a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group or a C₂₋₈ alkynyl group,each of which is substituted by substituent(s) selected from(a) hydroxy,(b) optionally halogenated C₁₋₄ alkyloxy,

(c) —O—(CH₂)—OH,

(d) —O—(CH₂)_(n)—O—CO—NH₂,(e) —O—(CH₂)_(n)—O—C₁₋₄ alkyl,(f) —O—(CH₂)—SO₂— (optionally halogenated C₁₋₄ alkyl),(g) —O—(CH₂)—SO₂—C₆₋₁₈ aryl,(h) —O—(CH₂)_(n)—SO₂—(CH₂)_(n)—OH,(i) —O—(CH₂)_(n)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(j) —CO—NR⁸—(CH₂)_(n)—OH,(k) —CO—NR⁸—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),

(l) —NR⁶R⁷,

(m) —NR⁸—(CH₂)_(n)—OH,(n) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(o) —NR⁸—CO—(CH₂)_(n)—OH,(p) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(q) —NR⁸—CO—(CH₂)—SO— (optionally halogenated C₁₋₄ alkyl),(r) —NR⁸—CO—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(s) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(t) —NR⁸—CO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(u) —NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(v) —NR⁸—SO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(w) —S— (CH₂)_(n)—OH,(x) —SO—(CH₂)_(n)—OH,(y) —SO₂—(CH₂)_(n)—OH, and(z) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—NH—C₁₋₄ alkyl,—CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂ and the like),wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or differentand each is a hydrogen atom or a C₁₋₄ alkyl group, R⁸ is a hydrogen atomor a C₁₋₄ alkyl group, and (CH₂)_(n) is optionally substituted by C₁₋₄alkyl or hydroxy;R³ is a hydrogen atom or a C₁₋₆ alkyl group; orR¹ and R² are optionally bonded to form

R² and R³ are optionally bonded to form C₂₋₄ alkylene.

Particularly preferably, R² is a C₁₋₈ alkyl group, a C₂₋₈ alkenyl groupor a C₂₋₈ alkynyl group (particularly, a C₁₋₈ alkyl group), each ofwhich is substituted by substituent(s) selected from

(a) hydroxy,(b) optionally halogenated C₁₋₄ alkyloxy,(c) —O—(CH₂)_(n)—OH (wherein (CH₂)_(n) is optionally substituted byhydroxy),

(d) —O—(CH₂)—O—CO—NH₂,

(e) —O—(CH₂)—O—C₁₋₄ alkyl,(f) —O—(CH₂)—SO₂— (optionally halogenated C₁₋₄ alkyl),(g) —O—(CH₂)_(n)—SO₂—C₆₁₈ aryl,(h) —O—(CH₂)_(n)—SO₂—(CH₂)_(n)—OH,(i) —O—(CH₂)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(j) —CO—NR⁸— (CH₂)_(n)—OH,(k) —CO—NR⁸—(CH₂)—SO₂— (optionally halogenated C₁₋₄ alkyl),

(l) —NR⁶R⁷,

(m) —NR⁸—(CH₂)_(n)—OH,(n) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(o) —NR⁸—CO—(CH₂)_(n)—OH (wherein (CH₂)_(n) is optionally substituted byC₁₋₄ alkyl),(p) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(q) —NR⁸—CO—(CH₂)_(n)—SO— (optionally halogenated C₁₋₄ alkyl),(r) —NR⁸—CO—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl)(wherein (CH₂), is optionally substituted by C₁₋₄ alkyl),(s) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(t) —NR⁸—CO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(u) —NR⁸—CO—NH—(CH₂)—SO₂—C₁₋₄ alkyl,(v) —NR⁸—SO₂—(CH₂)—SO₂—C₁₋₄ alkyl,(w) —S—(CH₂)_(n)—OH,(x) —SO—(CH₂)_(n)—OH,(y) —SO₂—(CH₂)_(n)—OH, and(z) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—NH—C₁₋₄ alkyl,—CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂ and the like),wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or differentand each is a hydrogen atom or a C₁₋₄ alkyl group, and R⁸ is a hydrogenatom or a C₁₋₄ alkyl group, and the like is preferable.

[Compound (Ik)]

A compound (I) wherein

R² is (i) a C₅₋₈ alkyl group substituted by hydroxy,(ii) a C₁₋₈ alkyl group substituted by substituent(s) selected from(a) halogenated C₁₋₄ alkyloxy,(b) —O—(CH₂)_(n)—OH,(c) —O—(CH₂)_(n)—O—CO—NH₂,(d) —O—(CH₂)_(n)—O— (optionally halogenated C₁₋₄ alkyl),(e) —O—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(f) —O—(CH₂)_(n)—SO₂—C₆₋₁₈ aryl,(g) —O—(CH₂)_(n)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(h) —CO—NR⁸—(CH₂)_(n)—OH,(i) —CO—NR⁸—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(j) —NR⁸—(CH₂)—SO₂—C₁₋₄ alkyl,(k) —NR⁸—CO—(CH₂)_(n)—OH,(l) —NR⁸—CO—(CH₂)_(n)—O—C₁₋₄ alkyl,(m) —NR⁸—CO—(CH₂)_(n)—SO— (optionally halogenated C₁₋₄ alkyl),(n) —NR⁸—CO—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(o) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(p) —NR⁸—CO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(q) —NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(r) —NR⁸—SO₂—(CH₂)—SO₂—C₁₋₄ alkyl,(s) —S— (CH₂)_(n)—OH,(t) —SO—(CH₂)_(n)—OH,(u) —SO₂—(CH₂)_(n)—OH, and(v) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—NH—C₁₋₄ alkyl,—CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂ and the like),wherein n is an integer of 1 to 4, R⁸ is a hydrogen atom or a C₁₋₄ alkylgroup, and (CH₂)_(n) is optionally substituted by C₁₋₄ alkyl,(iii) a C₂₋₈ alkenyl group optionally substituted by hydroxy, or(iv) a C₂₋₈ alkynyl group optionally substituted by hydroxy.

Particularly preferably, R² is (i) a C₅₋₈ alkyl group substituted byhydroxy,

(ii) a C₁₋₈ alkyl group substituted by substituent(s) selected from(a) halogenated C₁₋₄ alkyloxy,(b) —O—(CH₂)_(n)—OH (wherein (CH₂)_(n) is optionally substituted byhydroxy),(c) —O—(CH₂)_(n)—O—CO—NH₂,(d) —O—(CH₂)_(n)—O— (optionally halogenated C₁₋₄ alkyl),(e) —O—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(f) —O—(CH₂)_(n)—SO₂—C₆₋₁₈ aryl,(g) —O—(CH₂)_(n)—NR⁸—SO₂— (optionally halogenated C₁₋₄ alkyl),(h) —CO—NR⁸—(CH₂)_(n)—OH,(i) —CO—NR⁸—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl),(j) —NR⁸—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(k) —NR⁸—CO—(CH₂)_(n)—OH (wherein (CH₂)_(n) is optionally substituted byC₁₋₄ alkyl),(l) —NR⁸—CO—(CH₂)—O—C₁₋₄ alkyl,(m) —NR⁸—CO—(CH₂)_(n)—SO— (optionally halogenated C₁₋₄ alkyl),(n) —NR⁸—CO—(CH₂)_(n)—SO₂— (optionally halogenated C₁₋₄ alkyl)(wherein (CH₂)_(n) is optionally substituted by C₁₋₄ alkyl),(o) —NR⁸—CO—(CH₂)_(n)—SO₂—C₃₋₈ cycloalkyl,(p) —NR⁸—CO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(q) —NR⁸—CO—NH—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(r) —NR⁸—SO₂—(CH₂)_(n)—SO₂—C₁₋₄ alkyl,(s) —S— (CH₂)_(n)—OH,(t) —SO—(CH₂)_(n)—OH,(u) —SO₂—(CH₂)_(n)—OH A and(v) —NR⁸—CO— (optionally substituted heterocyclic group)(preferably, said heterocyclic group is a 5- to 8-membered heterocyclicgroup having 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and an optionally oxidized sulfur atom, which is optionallysubstituted by substituent(s) selected from hydroxy, C₁₋₄ alkyl,optionally oxidized C₁₋₄ alkylthio, —CO—C₁₋₄ alkyl, —CO—NH—C₁₋₄ alkyl,—CONH₂, —SO₂—C₁₋₄ alkyl, —SO₂—NH—C₁₋₄ alkyl, —SO₂NH₂ and the like),wherein n is an integer of 1 to 4, and R⁶ is a hydrogen atom or a C₁₋₄alkyl group,(iii) a C₂₋₈ alkenyl group optionally substituted by hydroxy, or(iv) a C₂₋₈ alkynyl group optionally substituted by hydroxy.

As the salts of the compound represented by the formula (I), forexample, metal salt, ammonium salt, salts with organic base, salts withinorganic acid, salts with organic acid, salts with basic or acidicamino acid and the like can be mentioned. As preferable examples of themetal salt, for example, alkali metal salts such as sodium salt,potassium salt and the like; alkaline earth metal salts such as calciumsalt, magnesium salt, barium salt and the like; aluminum salt and thelike can be mentioned. As preferable examples of the salts with organicbase, for example, salts with trimethylamine, triethylamine, pyridine,picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine,tromethamine [tris(hydroxymethyl)methylamine], t-butylamine,cyclohexylamine, dicyclohexylamine, N,N′-dibenzylethylenediamine and thelike can be mentioned. As preferable examples of salts with inorganicacid, for example, salts with hydrochloric acid, hydrobromic acid,nitric acid, sulfuric acid, phosphoric acid and the like can bementioned. As preferable examples of the salts with organic acid, forexample, salts with formic acid, acetic acid, trifluoroacetic acid,phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid,citric acid, succinic acid, malic acid, methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid and the like can bementioned. As preferable examples of the salts with basic amino acid,for example, salts with arginine, lysine, ornithine and the like can bementioned, and as preferable examples of the salts with acidic aminoacid, for example, salts with aspartic acid, glutamic acid and the likecan be mentioned.

Of these, pharmaceutically acceptable salts are preferable. For example,when a compound contains an acidic functional group, inorganic saltssuch as alkali metal salts (e.g., sodium salt, potassium salt etc.),alkaline earth metal salts (e.g., calcium salt, magnesium salt, bariumsalt etc.) and the like, ammonium salt and the like, and when a compoundcontains a basic functional group, for example, salts with inorganicacid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid, phosphoric acid and the like, or salts with organic acid such asacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid,maleic acid, citric acid, succinic acid, methanesulfonic acid,p-toluenesulfonic acid and the like can be mentioned.

As compound (I), preferred is a compound wherein A is an aryl groupsubstituted by a group of the formula —Y²—B and optionally furthersubstituted, wherein Y² is a single bond, —O—, —OCH₂—, —NH— or —S—, andB is an aryl group, a heterocyclic group, a C₃₋₈ cycloalkyl group, acarbamoyl group, a ureido group, a C₆₋₁₈ aryl-carbonyl group or a C₆₋₁₈aryl-C₁₋₄ alkyl-carbonyl group, each of which is optionally substituted.

As a preferable embodiment of compound (I), a compound wherein W isC(R¹);

A is an aryl group substituted by a group of the formula —Y²—B, andoptionally further substituted, wherein Y² is a single bond, —O—,—OCH₂—, —NH— or —S—, and B is an aryl group, a heterocyclic group, aC₃₋₈ cycloalkyl group, a carbamoyl group, a ureido group, a C₆₋₁₈aryl-carbonyl group or a C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group, each ofwhich is optionally substituted;R¹ is a group of the formula —X²—R⁴ wherein X² is a single bond, —NH— or—O—, and R⁴ is hydrogen atom or a C₁₋₈ alkyl group, a C₂₋₈ alkenylgroup, a C₂₋₈ alkynyl group, a carbamoyl group, a C₁₋₈ alkyl-carbonylgroup, a C₃₋₈ cycloalkyl group, a C₆₋₁₈ aryl group, a C₆₋₁₈ aryl-C₁₋₄alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈ aryl-C₁₋₄alkyl-carbonyl group, a heterocyclic group, a heterocycle-C₁₋₄ alkylgroup, a heterocycle-carbonyl group or a heterocycle-C₁₋₄ alkyl-carbonylgroup, each of which is optionally substituted;R² is hydrogen atom or a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₂₋₈alkynyl group, a carbamoyl group, a C₁₋₁₈ alkyl-carbonyl group, a C₁₋₈alkylsulfonyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₈ aryl group, aC₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈aryl-C₁₋₄ alkyl-carbonyl group, a C₆₋₁₈ aryl-sulfonyl group, aheterocyclic group, a heterocycle-C₁₋₄ alkyl group, aheterocycle-carbonyl group or a heterocycle-C₁₋₄ alkyl-carbonyl group,each of which is optionally substituted; andX¹ is —NR³— wherein R³ is a hydrogen atom or an optionally substitutedaliphatic hydrocarbon group can be mentioned.

As another preferable embodiment of compound (I), a compound wherein Wis N;

X¹ is —NR³— wherein R³ is a hydrogen atom or an optionally substitutedaliphatic hydrocarbon group;A is an aryl group substituted by a group of the formula —Y²—B andoptionally further substituted wherein Y² is a single bond, —O—, —OCH₂—,—NH— or —S—, and B is an aryl group, a heterocyclic group, a C₃₋₈cycloalkyl group, a carbamoyl group, a ureido group, a C₆₋₁₈aryl-carbonyl group or a C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group, each ofwhich is optionally substituted; andR² is a hydrogen atom or a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, aC₂₋₈ alkynyl group, a carbamoyl group, a C₁₋₈ alkyl-carbonyl group, aC₁₋₈ alkylsulfonyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₈ aryl group, aC₆₋₁₈ aryl-C₁₋₄ alkyl group, a C₆₋₁₈ aryl-carbonyl group, a C₆₋₁₈aryl-C₁₋₄ alkyl-carbonyl group, a C₆₋₁₈ aryl-sulfonyl group, aheterocyclic group, a heterocycle-C₁₋₄ alkyl group, aheterocycle-carbonyl group or a heterocycle-C₁₋₄ alkyl-carbonyl group,each of which is optionally substituted can be mentioned.

As a yet another preferable embodiment of compound (I), a compoundwherein W is N;

X¹ is —NR³—;

A is an aryl group substituted by a group of the formula —Y²—B andoptionally further substituted wherein Y² is a single bond, —O—, —OCH₂—,—NH— or —S—, and B is an aryl group, a heterocyclic group, a C₃₋₈cycloalkyl group, a carbamoyl group, a ureido group, a C₆₋₁₈aryl-carbonyl group or a C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl group, each ofwhich is optionally substituted; andR² and R³ are bonded to form an optionally substituted ring structurecan be mentioned.

[Production Methods]

The production methods of compound (I) of the present invention aredescribed in the following.

The compound (I) of the present invention the present invention can beobtained by, for example, the method shown by in the following schemesor a method analogous thereto and the like.

The compounds (II)-(VIII) in the schemes include salts, and as suchsalts, for example, those similar to the salts of compound (I) and thelike can be used.

The compound obtained in each step can be used as a reaction mixture oras a crude product in the next reaction. In addition, the compound canbe isolated from a reaction mixture according to a conventional method,and can be easily purified by a separation means such asrecrystallization, distillation, chromatography and the like.

A schematic reaction formulas are shown in the following, wherein eachsymbol of the compounds is as defined above.

The compound (I) of the present invention can be produced by, forexample, reacting a compound represented by the formula:

wherein L is a leaving group and other symbols are as defined above, ora salt thereof with a compound represented by the formula:

G-X¹-A  (III)

wherein G is a hydrogen atom or a metal atom, and other symbols are asdefined above, or a salt thereof.

When X¹ is —NR³—Y¹—, —O— or —S—, G is mainly a hydrogen atom, but may bean alkali metal such as lithium, sodium, potassium, cesium and the like,or an alkaline earth metal such as magnesium, calcium and the like. WhenX¹ is —CHR³—, G is preferably a metal such as lithium, halogenatedmagnesium, copper, zinc and the like.

The compound (III) or a salt thereof is preferably used in an amount of1-5 equivalents, preferably 1-2 equivalents, relative to compound (II)and the reaction is preferably carried out in a solvent. In addition, abase or an ammonium salt may be used in an amount of about 1-10equivalents, preferably 1-2 equivalents.

In the aforementioned formula, as a leaving group represented by L, ahalogen atom such as chlorine, bromine, iodine and the like, a group ofthe formula: —S(O)_(k)R^(a) wherein k is 0, 1 or 2, and R^(a) is a lower(C₁₋₄)alkyl group such as methyl, ethyl, propyl and the like, benzylgroup, a C₆₋₁₀ aryl group such as, phenyl, tolyl and the like, or agroup of the formula: —OR^(a) wherein R^(a) is as defined above, and thelike can be used.

As a solvent in the aforementioned reaction, for example, halogenatedhydrocarbons such as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane and the like, aromatic hydrocarbons such as benzene,toluene, xylene and the like, alcohols such as methanol, ethanol,isopropanol, t-butanol, phenol and the like, ethers such as diethylether, tetrahydrofuran, dioxane and the like, acetone, acetonitrile,ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide,1-methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide,water or a mixed solvent thereof and the like can be used.

As a base in the aforementioned reaction, an inorganic base, an organicbase and the like can be used. Specifically, for example, sodiumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine,N-ethyldiisopropylamine, pyridine, N,N-dimethylaminopyridine, sodiummethoxide, sodium ethoxide, potassium t-butoxide, sodium hydride, sodiumamide, diazabicycloundecene (DBU) and the like can be used.

As an ammonium salt in the aforementioned reaction, pyridinehydrochloride, pyridine hydrobromide, pyridine p-toluenesulfonate,quinoline hydrochloride, isoquinoline hydrochloride, pyrimidinehydrochloride, pyrazine hydrochloride, triazine hydrochloride,trimethylamine hydrochloride, triethylamine hydrochloride,N-ethyldiisopropylamine hydrochloride and the like can be used.

The aforementioned reaction can be carried under cooling, at roomtemperature or under heating (about 40-200° C., preferably about 40-160°C.), the reaction time is generally about 1-30 hr, preferably about 1-20hr, more preferably about 1-10 hr.

A compound (I) wherein X¹ is —SO— or —SO₂— can be produced by subjectinga compound (I) wherein X¹ is —S— to an oxidation reaction. As anoxidizing agent therefor, for example, m-chloroperbenzoic acid, hydrogenperoxide, peracetic acid, t-butyl hydroperoxide, potassiumperoxysulfate, potassium permanganate, sodium perborate, sodiumperiodate, sodium hypochlorite, halogen and the like can be used. When acompound (I) wherein X¹ is —SO— is produced, an oxidizing agent is usedin an amount of about 1-1.5 equivalents relative to a starting compound,and when a compound (I) wherein X¹ is —SO₂— is produced, it is used inan amount of about 2-3 equivalents relative to a starting compound. Thereaction solvent is not particularly limited as long as it does notreact with the oxidizing agent and, for example, halogenatedhydrocarbons such as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane and the like, aromatic hydrocarbons such as benzene,toluene, xylene and the like, alcohols such as methanol, ethanol,isopropanol, t-butanol and the like, ethers such as diethyl ether,tetrahydrofuran, dioxane and the like, carboxylic acids such as aceticacid, trifluoroacetic acid and the like, acetonitrile, ethyl acetate,N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone,dimethyl sulfoxide, water or a mixed solvent thereof and the like can beused. The reaction is carried out under cooling, at room temperature orunder heating, and the reaction time is generally about 1-20 hr,preferably about 1-10 hr.

A compound within the scope of the present invention can be alsoproduced by applying means known per se to the obtained compound of thepresent invention (I) for introduction of substituents and conversion offunctional groups. For conversion of substituents, a known conventionalmethod can be used. For example, conversion to carboxy group byhydrolysis of ester, conversion to carbamoyl group by amidation ofcarboxy group, conversion to hydroxymethyl group by reduction of carboxygroup, conversion to alcohol compound by reduction or alkylation ofcarbonyl group, reductive amination of carbonyl group, oximation ofcarbonyl group, acylation of amino group, alkylation of amino group,substitution and amination of active halogen by amine, alkylation ofhydroxy group, substitution and amination of hydroxy group and the likecan be mentioned. When a reactive substituent that causes non-objectreaction is present during the introduction of substituents andconversion of functional groups, a protecting group is introduced inadvance as necessary into the reactive substituent by a means known perse, and the protecting group is removed by a means known per se afterthe object reaction, whereby the compound within the scope of thepresent invention can be also produced.

The compound (I), which is a product of the reaction, may be produced asa single compound or as a mixture.

The compound (I) of the present invention thus obtained can be subjectedto a means known per se, such as solvent extraction, concentration,neutralization, filtration, crystallization, recrystallization, columnchromatography, high performance liquid chromatography and the like,whereby the object compound can be isolated and purified at high purityfrom a reaction mixture.

As the starting compound (III) of this production method, a commerciallyavailable one is used or can be produced by a means known per se.

The starting compound (II) of this production method can be produced by,for example, a method shown by the following scheme. Here, compounds(IIa), (IIb), (IIc), (IId) and (IIe) are encompassed in compound (II).

wherein L¹ and L² are halogen atoms, R^(a) is as defined above and t is1 or 2.

As Method A, compound (IIa) can be produced by reacting compound (IV)with a halogenating agent. As Method B, compound (IV) is reacted with anthionating agent to give compound (V), which is then reacted with acompound represented by R^(a)L² in the presence of a base to givecompound (IIb), which is further subjected to an oxidation reaction togive compound (IIc). As Method C, compound (IIa) is reacted with acompound represented by R^(a)OH in the presence of a base to givecompound (IId).

As the halogenating agent in Method A, for example, about 1-100equivalents of phosphorus oxychloride, phosphorus pentachloride,phosphorus trichloride, thionyl chloride, sulfuryl chloride, phosphorustribromide and the like can be used. In this case, the reaction may becarried out in the presence of a base such as diethylaniline,dimethylaniline, pyridine and the like. While the reaction may becarried out without solvent, as a reaction solvent, for example,halogenated hydrocarbons such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane and the like, aromatic hydrocarbonssuch as benzene, toluene, xylene and the like, ethers such as diethylether, tetrahydrofuran, dioxane and the like, acetonitrile, ethylacetate and the like may be used. The reaction is carried out undercooling, at room temperature or under heating, and the reaction time isgenerally about 1-20 hr, preferably about 1-10 hr.

As the thionating agent used in the production step from compound (IV)to compound (V) in Method B, for example, about 1-5 equivalents of aLawesson reagent, phosphorus pentasulfide and the like can be used. Asthe reaction solvent, for example, halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like, aromatic hydrocarbons such as benzene, toluene, xylene andthe like, ethers such as diethyl ether, tetrahydrofuran, dioxane and thelike, and the like can be used. The reaction is carried out at roomtemperature or under heating, and the reaction time is generally about1-20 hr, preferably about 1-10 hr.

As R^(a)L² in the production step from compound (V) to compound (IIb) inMethod B, for example, about 1-5 equivalents of methyl iodide, benzylchloride, benzyl bromide and the like can be used, and as the base, forexample, sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate, sodium hydrogen carbonate, potassium hydrogencarbonate, triethylamine, N-ethyldiisopropylamine, pyridine,N,N-dimethylaminopyridine, sodium methoxide, sodium ethoxide, potassiumt-butoxide, sodium hydride, sodium amide, diazabicycloundecene (DBU) andthe like can be used. As the reaction solvent, for example, halogenatedhydrocarbons such as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane and the like, aromatic hydrocarbons such as benzene,toluene, xylene and the like, alcohols such as methanol, ethanol,isopropanol, t-butanol and the like, ethers such as diethyl ether,tetrahydrofuran, dioxane and the like, acetone, acetonitrile, ethylacetate, N,N-dimethylformamide, N,N-dimethylacetamide,1-methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide,water or a mixed solvent thereof and the like can be used. The reactionis carried out under cooling, at room temperature or under heating, andthe reaction time is generally about 1-20 hr, preferably about 1-10 hr.

As the oxidizing agent in the production step from compound (IIb) tocompound (IIc) in Method B, for example, m-chloroperbenzoic acid,hydrogen peroxide, peracetic acid, t-butyl hydroperoxide, potassiumperoxysulfate, potassium permanganate, sodium perborate, sodiumperiodate, sodium hypochlorite, halogen and the like can be used. Whencompound (IIc) wherein t=1 is produced, an oxidizing agent is used inabout 1-1.5 equivalents relative to compound (IIb), and when compound(IIc) wherein t=2 is produced, it is used in about 2-3 equivalentsrelative to compound (IIb). The reaction solvent is not particularlylimited as long as it does not react with the oxidizing agent and, forexample, halogenated hydrocarbons such as dichloromethane, chloroform,carbon tetrachloride, 1,2-dichloroethane and the like, aromatichydrocarbons such as benzene, toluene, xylene and the like, alcoholssuch as methanol, ethanol, isopropanol, t-butanol and the like, etherssuch as diethyl ether, tetrahydrofuran, dioxane and the like, carboxylicacids such as acetic acid, trifluoroacetic acid and the like,acetonitrile, ethyl acetate, N,N-dimethylformamide,N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, wateror a mixed solvent thereof and the like can be used. The reaction iscarried out under cooling, at room temperature or under heating, and thereaction time is generally about 1-20 hr, preferably about 1-10 hr.

As R^(a)OH in the production step from compound (IIa) to compound (IId)in Method C, for example, about 1-10 equivalents of methanol, ethanol,phenol and the like can be used, and as a base, for example, sodiumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine,N-ethyldiisopropylamine, pyridine, N,N-dimethylaminopyridine, sodiummethoxide, sodium ethoxide, potassium t-butoxide, sodium hydride, sodiumamide, diazabicycloundecene (DBU) and the like can be used. As areaction solvent, for example, halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like, aromatic hydrocarbons such as benzene, toluene, xylene andthe like, ethers such as diethyl ether, tetrahydrofuran, dioxane and thelike, acetone, acetonitrile, ethyl acetate, N,N-dimethylformamide,N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide,hexamethylphosphoramide, water or a mixed solvent thereof and the likecan be used. The reaction is carried out under cooling, at roomtemperature or under heating, and the reaction time is generally about1-20 hr, preferably about 1-10 hr.

Furthermore, compound (IV) can be produced by, for example, a methodshown by the following formula:

wherein R¹⁰ is a C₁₋₄ alkyl group, and other symbols are as definedabove.

That is, compound (VI) is reacted in the presence of about 1-4equivalents of formamidine or a salt thereof, whereby compound (IV) canbe produced. As the reaction solvent, for example, alcohols such asmethanol, ethanol, isopropanol, t-butanol and the like, halogenatedhydrocarbons such as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane and the like, aromatic hydrocarbons such as benzene,toluene, xylene and the like, ethers such as diethyl ether,tetrahydrofuran, dioxane and the like, acetone, acetonitrile, ethylacetate, N,N-dimethylformamide, N,N-dimethylacetamide,1-methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide,water or a mixed solvent thereof and the like can be used. The reactionis carried out under cooling, at room temperature or under heating, andthe reaction time is generally about 1-20 hr, preferably about 1-10 hr.

When W is C(R¹), compound (II) can be also produced by, for example, amethod shown by the following formula:

wherein L³ is a halogen atom, and other symbols are as defined above.

For a step in this method to produce compound (VIII) from compound(VII), a reaction generally known as a Sonogashira reaction or areaction analogous thereto can be used and generally, compound (VIII)can be produced by reacting compound (VII) with about 1-3 equivalents ofa compound represented by the formula

in the presence of a base, about 0.01-1 equivalent of a palladiumcatalyst and copper iodide. As the base, for example, triethylamine,N-ethyldiisopropylamine, diisopropylamine, pyridine,N,N-dimethylaminopyridine, diazabicycloundecene (DBU), sodium carbonate,potassium carbonate, sodium hydrogen carbonate, potassium hydrogencarbonate and the like can be used. As the palladium catalyst, forexample, dichlorobis(triphenylphosphine)palladium(II), palladium oncarbon, palladium(II) diacetate, bis(benzonitrile)dichloropalladium(II)and the like can be used. This reaction may be carried out in theco-presence of a tertiary phosphine compound such as triphenylphosphine,tributylphosphine and the like as a ligand. As the reaction solvent, forexample, halogenated hydrocarbons such as dichloromethane, chloroform,carbon tetrachloride, 1,2-dichloroethane and the like, aromatichydrocarbons such as benzene, toluene, xylene and the like, alcoholssuch as methanol, ethanol, isopropanol, t-butanol and the like, etherssuch as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane andthe like, acetone, acetonitrile, ethyl acetate, N,N-dimethylformamide,N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide,hexamethylphosphoramide, water or a mixed solvent thereof and the likecan be used. This reaction is carried out at room temperature or underheating and the reaction time is generally about 1-50 hr, preferablyabout 1-20 hr.

For a step in this method to produce compound (IIe) from compound(VIII), generally, cyclization reaction is conducted in the presence ofabout 1-3 equivalents of base or about 0.01-1 equivalent of copperiodide to give compound (IIe). As the base, for example, potassiumt-butoxide, sodium t-butoxide, cesium t-butoxide, sodium ethoxide,potassium hydride, sodium hydride, cesium hydroxide, sodium hydroxide,potassium hydroxide, sodium carbonate, potassium carbonate, sodiumhydrogen carbonate, potassium hydrogen carbonate, triethylamine,N-ethyldiisopropylamine, diisopropylamine, pyridine,N,N-dimethylaminopyridine, diazabicycloundecene (DBU) and the like canbe used. As the reaction solvent, for example, halogenated hydrocarbonssuch as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane and the like, aromatic hydrocarbons such as benzene,toluene, xylene and the like, alcohols such as methanol, ethanol,isopropanol, t-butanol and the like, ethers such as diethyl ether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like, acetone,acetonitrile, ethyl acetate, N,N-dimethylformamide,N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide,hexamethylphosphoramide, water or a mixed solvent thereof and the likecan be used. The reaction is carried out at low temperature, at roomtemperature or under heating and the reaction time is generally about1-50 hr, preferably about 1-20 hr.

Depending on the kind of the substituent of starting compound (II), astarting compound (II) having a different substituent can be produced bysubstituent conversion from, as a starting material, a compound producedby the above-mentioned production method. For the substituentconversion, a known general method can be used. For example, conversionto carbamoyl group by hydrolysis and amidation of ester, conversion tohydroxymethyl group by reduction of carboxy group, conversion to alcoholcompound by reduction or alkylation of carbonyl group, reductiveamination of carbonyl group, oximation of carbonyl group, acylation ofamino group, alkylation of amino group, substitution and amination ofactive halogen by amine, alkylation of hydroxy group, substitution andamination of hydroxy group and the like can be mentioned. When areactive substituent that causes non-object reaction is present duringthe introduction of substituents and conversion of functional groups, aprotecting group is introduced in advance as necessary into the reactivesubstituent by a means known per se, and the protecting group is removedby a means known per se after the object reaction, whereby the startingcompound (II) can be also produced.

Thus-obtained compound (I) can be isolated and purified by a separationmeans known per se, such as concentration, concentration under reducedpressure, solvent extraction, crystallization, recrystallization, phasetransfer, chromatography and the like.

If compound (I) is obtained as a free form, it can be converted into adesired salt by a method known per se or a modification thereof;conversely, if compound (I) is obtained as a salt, it can be convertedinto a free form or another desired salt by a method known per se or amodification thereof.

When compound (I) has isomers such as optical isomer, stereoisomer,positional isomer, rotational isomer and the like, and any isomers andmixtures are encompassed in the compound (I). For example, when compound(I) has an optical isomer, an optical isomer separated from a racemateis also encompassed in the compound (I). These isomers can be obtainedas independent products by a synthesis means or a separation means(concentration, solvent extraction, column chromatography,recrystallization and the like) known per se.

The compound (I) may be a crystal, and both a single crystal and crystalmixtures are encompassed in the compound (I). Crystals can be producedby crystallization according to crystallization methods known per se.

The compound (I) may be a solvate (e.g., hydrate etc.) or a non-solvate,both of which are encompassed in the compound (I).

A compound labeled with an isotope (e.g., ³H, ¹⁴C, ³⁵S, ¹²⁵I and thelike) is also encompassed in the compound (I).

A prodrug of the compound (I) or a salt thereof (hereinafter referred toas compound (I)) means a compound which is converted to the compound (I)with a reaction due to an enzyme, an gastric acid, etc. under thephysiological condition in the living body, that is, a compound which isconverted to the compound (I) with oxidation, reduction, hydrolysis,etc. according to an enzyme; a compound which is converted to thecompound (I) by hydrolysis etc. due to gastric acid, etc. A prodrug forcompound (I) may be a compound obtained by subjecting an amino group incompound (I) to an acylation, alkylation or phosphorylation (e.g., acompound obtained by subjecting an amino group in compound (I) to aneicosanoylation, alanylation, pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylationand tert-butylation, etc.); a compound obtained by subjecting a hydroxygroup in compound (I) to an acylation, alkylation, phosphorylation orboration (e.g., a compound obtained by subjecting an hydroxy group incompound (1) to an acetylation, palmitoylation, propanoylation,pivaloylation, succinylation, fumarylation, alanylation,dimethylaminomethylcarbonylation, etc.); a compound obtained bysubjecting a carboxyl group in compound (I) to an esterification oramidation (e.g., a compound obtained by subjecting a carboxyl group incompound (I) to an ethyl esterification, phenyl esterification,carboxymethyl esterification, dimethylaminomethyl esterification,pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification,phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification, cyclohexyloxycarbonylethyl esterification andmethylamidation, etc.) and the like. Any of these compounds can beproduced from compound (I) by a method known per se.

A prodrug for compound (I) may also be one which is converted intocompound (I) under a physiological condition, such as those described inIYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol. 7, Design ofMolecules, p. 163-198, Published by HIROKAWA SHOTEN (1990).

The compound (I) of the present invention, or a salt thereof or aprodrug thereof (hereinafter referred to as the compound of the presentinvention) possesses tyrosine kinase-inhibiting activity and can be usedfor the prophylaxis or treatment of treat tyrosine kinase-dependentdiseases in mammals. Tyrosine kinase-dependent diseases include diseasescharacterized by increased cell proliferation due to abnormal tyrosinekinase enzyme activity. Furthermore, the compound of the presentinvention specifically inhibits HER2 kinase and/or EGFR kinase and istherefore also useful as a therapeutic agent for suppressing the growthof HER2 and/or EGFR kinase-expressing cancer, or a preventive agent forpreventing the transition of hormone-dependent cancer tohormone-independent cancer. In addition, the compound is useful as apharmaceutical agent because it shows low toxicity (e.g., acutetoxicity, chronic toxicity, genetic toxicity, reproductive toxicity,cardiotoxicity, drug interaction, carcinogenicity and the like), highwater solubility, and is superior in stability, pharmacokinetics(absorption, distribution, metabolism, excretion and the like) andefficacy expression.

Accordingly, the compound of the present invention can be used as a safeagent for the prophylaxis or treatment of diseases due to abnormal cellproliferation such as various cancers (particularly breast cancer,prostate cancer, pancreatic cancer, gastric cancer, lung cancer, coloncancer, rectal cancer, esophagus cancer, duodenal cancer, cancer of thetongue, cancer of pharynx, cerebral tumor, neurilemoma, non-small celllung cancer, small cell lung cancer, liver cancer, kidney cancer, cancerof the bile duct, cancer of the uterine body, cancer of the uterinecervix, ovarian cancer, urinary bladder cancer, skin cancer, hemangioma,malignant lymphoma, malignant melanoma, thyroid cancer, bone tumors,vascular fibroma, retinoblastoma, penile cancer, solid cancer inchildhood, Kaposi's sarcoma, Kaposi's sarcoma derived from AIDS,maxillary tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma,leukemia, etc.), atherosclerosis, angiogenesis (e.g., angiogenesisassociated with growth of solid cancer and sarcoma, angiogenesisassociated with tumor metastasis, and angiogenesis associated withdiabetic retinopathy, etc.), and viral diseases (HIV infection etc.).

Tyrosine kinase-dependent diseases further include cardiovasculardiseases associated with abnormal tyrosine kinase enzyme activity. Thecompound of the present invention can therefore be used as an agent forprophylaxis or treatment of cardiovascular diseases such as restenosis.

The compound of the present invention is useful as an anticancer agentfor the prophylaxis or treatment of cancer, especially e.g., breastcancer, prostate cancer, pancreatic cancer, gastric cancer, lung cancer,colon cancer, colorectal cancer, kidney cancer and the like.

The compound of the present invention shows low toxicity and can be usedas a pharmaceutical agent as it is, or as a pharmaceutical compositionin admixture with a commonly known pharmaceutically acceptable carrieretc. in mammals (e.g., humans, horses, bovines, dogs, cats, rats, mice,rabbits, pigs, monkeys, and the like).

In addition to the compound of the present invention, saidpharmaceutical composition may contain other active ingredients, e.g.,the following hormonal therapeutic agents, anticancer agent (e.g.,chemotherapeutic agents, immunotherapeutic agents, or pharmaceuticalagents inhibiting the action of cell growth factors or cell growthfactor receptors), and the like.

As a pharmaceutical agent for mammals such as humans, the compound ofthe present invention can be administered orally in the form of, forexample, tablets, capsules (including soft capsules and microcapsules),powders, granules and the like, or parenterally in the form ofinjections, suppositories, pellets and the like. Examples of the“parenteral administration route” include intravenous, intramuscular,subcutaneous, intra-tissue, intranasal, intradermal, instillation,intracerebral, intrarectal, intravaginal, intraperitoneal, intratumoral,juxtaposition of tumor and administration directly to the lesion.

The dose of the compound of the present invention varies depending onthe route of administration, symptoms, etc. For example, when it isadministered orally as an anticancer agent to a patient (body weight 40to 80 kg) with breast cancer or prostate cancer, its dose is, forexample, 0.5 to 100 mg/kg body weight per day, preferably 1 to 50 mg/kgbody weight per day, and more preferably 1 or 25 mg/kg body weight perday. This amount may be administered once or in 2 to 3 divided portionsdaily.

The compound of the present invention can be safely administered orallyor parenterally (e.g., topical, rectal, intravenous administrationsetc.) as a single agent, or a pharmaceutical composition containing apharmacologically acceptable carrier according to a conventional method(e.g., a method described in the Japanese Pharmacopoeia etc.), such astablet (including sugar-coated tablet, film-coated tablet), powder,granule, capsule, liquid, emulsion, suspension, injection, suppository,sustained release preparation, plaster and the like.

And a combination of (1) administering an effective amount of a compoundof the present invention and (2) 1 to 3 selected from the groupconsisting of (i) administering an effective amount of other anticanceragents, (ii) administering an effective amount of hormonal therapeuticagents and (iii) non-drug therapy can prevent and/or treat cancer moreeffectively. As the non-drug therapy, for example, surgery,radiotherapy, gene therapy, thermotherapy, cryotherapy, lasercauterization, and the like are exemplified and two or more of these maybe combined.

For example, the compound of the present invention can be administeredto the same subject simultaneously with hormonal therapeutic agents,anticancer agents (e.g., chemotherapeutic agents, immunotherapeuticagents, or pharmaceutical agents inhibiting the action of cell growthfactors or cell growth factor receptors) (hereafter, these are referredto as a concomitant drug).

Although the compound of the present invention exhibits excellentanticancer action even when used as a simple agent, its effect can beenhanced by using it in combination with one or more of the concomitantdrug(s) mentioned above (multi-agent co-administration).

As examples of said “hormonal therapeutic agents,” there may bementioned fosfestrol, diethylstylbestrol, chlorotrianisene,medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate,cyproterone acetate, danazol, dienogest, asoprisnil, allylestrenol,gestrinone, nomegestrol, Tadenan, mepartricin, raloxifene, ormeloxifene,levormeloxifene, anti-estrogens (e.g., tamoxifen citrate, toremifenecitrate, and the like), ER down regulator (e.g., fulvestrant, and thelike), human menopausal gonadotrophin, follicle stimulating hormone,pill preparations, mepitiostane, testrolactone, aminoglutethimide, LH-RHagonists (e.g., goserelin acetate, buserelin, leuprorelin, and thelike), droloxifene, epitiostanol, ethinylestradiol sulfonate, aromataseinhibitors (e.g., fadrozole hydrochloride, anastrozole, retrozole,exemestane, vorozole, formestane, and the like), anti-androgens (e.g.,flutamide, bicartamide, nilutamide, and the like), 5α-reductaseinhibitors (e.g., finasteride, dutasteride, epristeride, and the like),adrenocorticohormone drugs (e.g., dexamethasone, prednisolone,betamethasone, triamcinolone, and the like), androgen synthesisinhibitors (e.g., abiraterone, and the like), retinoid and drugs thatretard retinoid metabolism (e.g., liarozole, and the like), etc. andLH-RH agonists (e.g., goserelin acetate, buserelin, leuprorelin) arepreferable.

As examples of said “chemotherapeutic agents”, there may be mentionedalkylating agents, antimetabolites, anticancer antibiotics,plant-derived anticancer agents, and the like.

As examples of “alkylating agents”, there may be mentioned nitrogenmustard, nitrogen mustard-N-oxide hydrochloride, chlorambutyl,cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfantosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan,dacarbazine, ranimustine, sodium estramustine phosphate,triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman,etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin,altretamine, ambamustine, dibrospidium hydrochloride, fotemustine,prednimustine, pumitepa, ribomustin, temozolomide, treosulphan,trophosphamide, zinostatin stimalamer, adozelesin, cystemustine,bizelesin, and the like.

As examples of “antimetabolites”, there may be mentioned mercaptopurine,6-mercaptopurine riboside, thioinosine, methotrexate, enocitabine,cytarabine, cytarabine ocfosfate, ancitabine hydrochloride, 5-FU drugs(e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur,gallocitabine, emmitefur, and the like), aminopterine, leucovorincalcium, tabloid, butocine, folinate calcium, levofolinate calcium,cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide,pentostatin, piritrexim, idoxuridine, mitoguazone, thiazophrine,ambamustine, and the like.

As examples of “anticancer antibiotics”, there may be mentionedactinomycin-D, actinomycin-C, mitomycin-C, chromomycin-A3, bleomycinhydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicinhydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride,pirarubicin hydrochloride, epirubicin hydrochloride, neocarzinostatin,mithramycin, sarcomycin, carzinophilin, mitotane, zorubicinhydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, andthe like.

As examples of “plant-derived anticancer agents”, there may be mentionedetoposide, etoposide phosphate, vinblastine sulfate, vincristinesulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel,vinorelbine, and the like.

As examples of said “immunotherapeutic agents (BRM)”, there may bementioned picibanil, krestin, sizofuran, lentinan, ubenimex,interferons, interleukins, macrophage colony-stimulating factor,granulocyte colony-stimulating factor, erythropoietin, lymphotoxin, BCGvaccine, Corynebacterium parvum, levamisole, polysaccharide K,procodazole, and the like.

The “growth factor” in said “pharmaceutical agents inhibiting the actionof cell growth factors or cell growth factor receptors”, there may bementioned any substances that promote cell proliferation, which arenormally peptides having a molecular weight of not more than 20,000 thatare capable of exhibiting their activity at low concentrations bybinding to a receptor, including (1) EGF (epidermal growth factor) orsubstances possessing substantially the same activity as it [e.g., EGF,heregulin (HER2 ligand), and the like], (2) insulin or substancespossessing substantially the same activity as it [e.g., insulin, IGF(insulin-like growth factor)-1, IGF-2, and the like], (3) FGF(fibroblast growth factor) or substances possessing substantially thesame activity as it [e.g., acidic FGF, basic FGF, KGF (keratinocytegrowth factor), FGF-10, and the like], (4) other cell growth factors[e.g., CSF (colony stimulating factor), EPO (erythropoietin), IL-2(interleukin-2), NGF (nerve growth factor), PDGF (platelet-derivedgrowth factor), TGFβ (transforming growth factor β), HGF (hepatocytegrowth factor), VEGF (vascular endothelial growth factor), and thelike], and the like.

As examples of said “growth factor receptors”, there may be mentionedany receptors capable of binding to the aforementioned growth factors,including EGF receptor, heregulin receptor (HER2), insulin receptor, IGFreceptor, FGF receptor-1 or FGF receptor-2, and the like.

As examples of said “pharmaceutical agents inhibiting the action of cellgrowth factor”, there may be mentioned trastuzumab (Herceptin (trademark): HER2 antibody), imatinib mesilate, ZD1839 or cetuximab, antibodyto VEGF (e.g., bevacizumab), antibody to VEGF receptor, gefitinib,erlotinib, and the like.

In addition to the aforementioned drugs, L-asparaginase, aceglatone,procarbazine hydrochloride, protoporphyrin-cobalt complex salt, mercurichematoporphyrin-sodium, topoisomerase I inhibitors (e.g., irinotecan,topotecan, and the like), topoisomerase II inhibitors (e.g., sobuzoxane,and the like), differentiation inducers (e.g., retinoid, vitamin D, andthe like), angiogenesis inhibitors (e.g., thalidomide, SU11248, and thelike), α-blockers (e.g., tamsulosin hydrochloride, naftopidil, urapidil,alfuzosin, terazosin, prazosin, silodosin, and the like),serine/threonine kinase inhibitor, endothelin receptor antagonist (e.g.,atrasentan, and the like), proteasome inhibitor (e.g., bortezomib, andthe like), Hsp 90 inhibitor (e.g., 17-AAG, and the like),spironolactone, minoxidil, 11α-hydroxyprogesterone, bone resorptioninhibiting/metastasis suppressing agent (e.g., zoledronic acid,alendronic acid, pamidronic acid, etidronic acid, ibandronic acid,clodronic acid) and the like can be used.

Of those mentioned above, LH-RH agonist (e.g., goserelin acetate,buserelin, leuprorelin, and the like), trastuzumab (HER2 antibody) andthe like are preferable as concomitant drugs.

In combination of the compound of the present invention and theconcomitant drug, the administration time of the compound of the presentinvention and the concomitant drug is not restricted, and the compoundof the present invention and the concomitant drug can be administered tothe administration subject simultaneously, or may be administered atdifferent times. The dosage of the concomitant drug may be determinedaccording to the administration amount clinically used, and can beappropriately selected depending on the administration subject,administration route, disease, combination and the like.

The administration mode of the compound of the present invention and theconcomitant drug is not particularly restricted, and it is sufficientthat the compound of the present invention and the concomitant drug arecombined in administration. Examples of such administration mode includethe following methods:

(1) The compound of the present invention and the concomitant drug aresimultaneously produced to give a single preparation which isadministered. (2) The compound of the present invention and theconcomitant drug are separately produced to give two kinds ofpreparations which are administered simultaneously by the sameadministration route. (3) The compound of the present invention and theconcomitant drug are separately produced to give two kinds ofpreparations which are administered by the same administration routeonly at the different times. (4) The compound of the present inventionand the concomitant drug are separately produced to give two kinds ofpreparations which are administered simultaneously by differentadministration routes. (5) The compound of the present invention and theconcomitant drug are separately produced to give two kinds ofpreparations which are administered by different administration routesat different times (for example, the compound of the present inventionand the concomitant drug are administered in this order, or in thereverse order).

EXAMPLES

The present invention is explained in detail by way of the followingReference Examples, Examples, Formulation Examples and ExperimentalExamples but these do not limit the present invention.

The elution in column chromatography in Reference Examples and Exampleswas performed under observation by TLC (thin-layer chromatography). Inthe TLC observation, Kieselgel 60F₂₅₄ plate (Merck) or NH TLC platemanufactured by Fuji Silysia Chemical Ltd. was used as a TLC plate, thesolvent used as an elution solvent in the column chromatography was usedas a developing solvent, and the means of detection used was an UVdetector. As silica gel for column, Kieselgel 60F₂₅₄ (70-230 mesh)manufactured by Merck or Chromatorex NH DM1020 (basic silica gel,100-200 mesh) manufactured by Fuji Silysia Chemical Ltd. was used. Theratio of solvents in silica gel chromatography is a volume ratio of thesolvents mixed. In addition, % means percentage by weight unlessotherwise specified.

NMR spectra are shown by proton NMR with tetramethylsilane as theinternal standard, using VARIAN Gemini-200 (200 MHz type spectrometer)or Gemini-300 (300 MHz type spectrometer) or BRUKER AVANCE300 (300 MHztype spectrometer); 6 values are expressed in ppm.

The abbreviations used in Reference Examples and Examples mean thefollowing:

s: singlet, br: broad, d: doublet, t: triplet, q: quartet, dd: doubledoublet, m: multiplet, J: coupling constant, Hz: hertz, DMSO: dimethylsulfoxide

Genetic manipulation methods described in Experimental Examples beloware based on the methods described in Maniatis et al., MolecularCloning, Cold Spring Harbor Laboratory, 1989, and the appended protocol.

Reference Example 1 Production of2-[(2-chloro-4-nitrophehoxy)methyl]benzonitrile

To a solution of 2-chloro-4-nitrophenol (3.5 g) and2-(bromomethyl)benzonitrile (4.0 g) in N,N-dimethylformamide (50 mL) wasadded potassium carbonate (3.7 g), and the mixture was stirred at roomtemperature for 30 min. After the completion of the reaction, water (50mL) was added, and the mixture was stirred for 10 min. The resultantpale-yellow solid was collected by filtration. The residue was washedwith diisopropyl ether, and dried to give the title compound (5.04 g) aspale-yellow crystals.

¹H-NMR (CDCl₃) δ 5.44 (2H, s), 7.13 (1H, d, J=9.0 Hz), 7.51 (1H, dt,J=1.2, 7.2 Hz), 7.68-7.80 (3H, m), 8.19 (1H, dd, J=2.7, 9.0 Hz), 8.35(1H, d, J=2.7 Hz).

Reference Example 2 Production of2-[(4-amino-2-chlorophenoxy)methyl]benzonitrile

To a solution of 2-[(2-chloro-4-nitrophenoxy)methyl]benzonitrile (2.0 g)in ethanol/water (9:1, 40 mL) was added calcium chloride (90%, 427 mg),and the mixture was stirred at 100° C. for 10 min. Reduced iron (90%,2.6 g) was added at room temperature, and the mixture was stirred at100° C. for 3 hrs. After the completion of the reaction, the reactionmixture was filtered (celite), and the filtrate was concentrated underreduced pressure. Water was added to the residue and the mixture wasdiluted with ethyl acetate and washed with water and saturated brine.The organic layer was dried over anhydrous magnesium sulfate, filteredand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane:ethyl acetate:methylenechloride=2:1:1) to give the title compound (1.2 g) as a white solid.

¹H-NMR (CDCl₃) δ 3.53 (2H, br s), 5.23 (2H, s), 6.54 (1H, dd, J=2.7, 8.7Hz), 6.76 (1H, d, J=2.7 Hz), 6.88 (1H, d, J=8.7 Hz), 7.42 (1H, dt,J=0.9, 7.8 Hz), 7.62-7.70 (2H, m), 7.81 (1H, d, J=7.8 Hz).

Reference Example 3 Production of2-[(2-methyl-4-nitrophenoxy)methyl]benzonitrile

The title compound (8.2 g) was obtained as a pale-yellow solid by thereaction in the same manner as in Reference Example 1 using2-methyl-4-nitrophenol (5.0 g) and 2-(bromomethyl)benzonitrile (6.4 g).

¹H-NMR (CDCl₃) δ 2.37 (3H, s), 5.36 (2H, s), 6.97 (1H, d, J=8.4 Hz),7.50 (1H, m), 7.65-7.69 (2H, m), 7.76 (1H, td, J=0.9, 7.5 Hz), 8.09-8.14(2H, m).

Reference Example 4 Production of2-[(4-amino-2-methylphenoxy)methyl]benzonitrile

The title compound (3.7 g) was obtained as a white solid by the reactionin the same manner as in Reference Example 2 using2-[(2-methyl-4-nitrophenoxy)methyl]benzonitrile (6.0 g), calciumchloride (90%, 1.3 g) and reduced iron (90%, 8.3 g).

¹H-NMR (CDCl₃) δ 2.24 (3H, s), 3.41 (2H, br s), 5.17 (2H, s), 6.48 (1H,dd, J=3.0, 8.4 Hz), 6.56 (1H, d, J=3.0 Hz), 6.73 (1H, d, J=8.4 Hz), 7.40(1H, dt, J=1.2, 7.5 Hz), 7.59-7.71 (3H, m).

Reference Example 5 Production of3-(2-chloro-4-nitrophenoxy)benzonitrile

To a solution of 2-chloro-1-fluoro-4-nitrobenzene (3.7 g) and3-hydroxybenzonitrile (2.5 g) in N,N-dimethylformamide (50 mL) was addedpotassium carbonate (4.4 g), and the mixture was stirred at 60° C. for 4hrs. After the completion of the reaction, water (50 mL) was added, andthe mixture was stirred for 10 min. The resultant pale-yellow solid wascollected by filtration, washed with diisopropyl ether, and dried togive the title compound (5.3 g) as pale-yellow crystals.

¹H-NMR (CDCl₃) δ 7.03 (1H, d, J=9.0 Hz), 7.27-7.33 (2H, m), 7.55-7.56(2H, m), 8.15 (1H, dd, J=2.7, 9.0 Hz), 8.42 (1H, d, J=2.7 Hz).

Reference Example 6 Production of3-(4-amino-2-chlorophenoxy)benzonitrile

To a solution of 3-(2-chloro-4-nitrophenoxy)benzonitrile (2.0 g) inethanol/water (9:1, 40 mL) was added calcium chloride (90%, 449 mg), andthe mixture was stirred at 100° C. for 10 min. Reduced iron (90%, 2.7 g)was added at room temperature, and the mixture was stirred at 100° C.for 5 hrs. After the completion of the reaction, the reaction mixturewas filtered (celite), and the filtrate was concentrated under reducedpressure. Water was added to the residue and the mixture was dilutedwith ethyl acetate and washed with water and saturated brine. Theorganic layer was dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=3:1) to give the titlecompound (1.25 g) as a white solid.

¹H-NMR (CDCl₃) δ 3.75 (2H, br s), 6.60 (1H, dd, J=2.7, 8.4 Hz), 6.80(1H, d, J=2.7 Hz), 6.92 (1H, d, J=8.4 Hz), 7.06 (1H, m), 7.14 (1H, m),7.30 (1H, td, J=1.2, 7.5 Hz), 7.37 (1H, d, J=7.5 Hz).

Reference Example 7 Production of ethyl 2-fluoro-5-nitrobenzoate

Under ice-cooling, thionyl chloride (8.02 mL) was added dropwise toethanol (200 mL), and 2-fluoro-5-nitrobenzoic acid (13.81 g) was added.This mixture was stirred at 80° C. for 4 hrs. and concentrated underreduced pressure. A saturated aqueous sodium hydrogen carbonate solutionwas added to the reaction mixture and the mixture was extracted withethyl acetate. The extract was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure to give the title compound (15.77 g) as a pale-yellowoil.

¹H-NMR (CDCl₃) δ: 1.43 (3H, t, J=7.2 Hz), 4.46 (2H, q, J=7.2 Hz), 7.32(1H, t, J=9.1 Hz), 8.41 (1H, ddd, J=9.1, 4.3, 3.0 Hz), 8.85 (1H, dd,J=6.1, 3.0 Hz)

Reference Example 8 Production of ethyl 5-amino-2-phenoxybenzoate

A mixture of ethyl 2-fluoro-5-nitrobenzoate (1.07 g), phenol (565 mg),potassium carbonate (1.38 g) and N,N-dimethylformamide (20 mL) wasstirred at 80° C. for 4 hrs. The reaction mixture was concentrated underreduced pressure. Water was added to the residue and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the obtained residue was purifiedby silica gel column chromatography (eluent, ethylacetate:hexane=20:80→30:70). The object fraction was concentrated underreduced pressure and ethanol (20 mL) and 10% palladium on carbon (1.5 g)were added to the residue (1.54 g). The mixture was stirred overnightunder a hydrogen stream. The catalyst was filtered off, and the filtratewas concentrated. The obtained residue was purified by silica gel columnchromatography (eluent, ethyl acetate:hexane=20:80→50:50) andrecrystallized from diisopropyl ether-hexane to give the title compound(1.07 g) as a pale-brown powder.

¹H-NMR (CDCl₃) δ: 1.12 (3H, t, J=7.2 Hz), 3.71 (2H, s), 4.17 (2H, q,J=7.2 Hz), 6.80-6.87 (3H, m), 6.91 (1H, d, J=8.5 Hz), 6.97 (1H, t, J=7.3Hz), 7.21-7.30 (3H, m).

Reference Example 9 Production of methyl4-{[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]methyl}benzoate andmethyl4-{[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoate

To a solution of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (400 mg) inN,N-dimethylformamide (8 mL) was added 60% sodium hydride (98 mg) underice-cooling, and the mixture was stirred at room temperature for 10 min.Then, methyl 4-(bromomethyl)benzoate (606 mg) was added underice-cooling, and the mixture was stirred at room temperature for 30 min.After the completion of the reaction, the mixture was diluted with ethylacetate and washed with saturated aqueous sodium hydrogen carbonate andsaturated brine. The organic layer was concentrated under reducedpressure, and the residue was subjected to silica gel columnchromatography (hexane:ethyl acetate=2:1→1:2) to give methyl4-{[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]methyl}benzoate (251mg) and methyl4-{[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoate (450mg) both as pale-yellow solids.

methyl4-{[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]methyl}benzoate:¹H-NMR (CDCl₃) δ 2.71 (3H, s), 3.89 (3H, s), 5.93 (2H, s), 7.22 (2H, d,J=8.1 Hz), 7.98 (2H, d, J=8.1 Hz), 8.23 (1H, s), 8.80 (1H, s).methyl4-{[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoate:¹H-NMR (CDCl₃) δ 2.73 (3H, s), 3.92 (3H, s), 5.69 (2H, s), 7.34 (2H, d,J=8.4 Hz), 8.03 (2H, d, J=8.4 Hz), 8.04 (1H, s), 8.73 (1H, s).

Reference Example 10 Production of2-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethyl benzoate and2-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]ethyl benzoate

To a solution of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (300 mg)and 2-iodoethyl benzoate (548 mg) in N,N-dimethylformamide (10 mL) wasadded potassium carbonate (374 mg), and the mixture was stirred at 60°C. for 1 hr. After the completion of the reaction, water was added tothe reaction mixture. The mixture was diluted with ethyl acetate andwashed with water and saturated brine. The organic layer was dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=3:2) to give2-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethyl benzoate (266mg) and 2-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]ethylbenzoate (191 mg) both as pale-yellow solids.

2-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethyl benzoate:¹H-NMR (CDCl₃) δ 2.66 (3H, s), 4.78 (2H, t, J=5.4 Hz), 5.06 (2H, t,J=5.4 Hz), 7.27-7.40 (2H, m), 7.53 (1H, m), 7.85-7.89 (2H, m), 8.20 (1H,s), 8.79 (1H, s).2-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]ethyl benzoate:¹H-NMR (CDCl₃) δ 2.73 (3H, s), 4.80-4.86 (4H, m), 7.40-7.46 (2H, m),7.58 (1H, m), 7.94-7.97 (2H, m), 8.20 (1H, s), 8.73 (1H, s).

Reference Example 11 Production of3-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]propyl benzoate and3-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]propyl benzoate

3-[7-(Methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]propyl benzoate (623mg) and 3-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]propylbenzoate (556 mg) were obtained both as pale-yellow solids by thereaction in the same manner as in Reference Example 10 using7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (600 mg), 3-iodopropylbenzoate (1.15 g) and potassium carbonate (748 mg).

3-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]propyl benzoate:¹H-NMR (CDCl₃) δ 2.40-2.47 (2H, m), 2.66 (3H, s), 4.42 (2H, t, J=5.7Hz), 4.88 (2H, t, J=7.2 Hz), 7.42-7.46 (2H, m), 7.57 (1H, m), 7.98-8.02(2H, m), 8.15 (1H, s), 8.73 (1H, s).3-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]propyl benzoate:¹H-NMR (CDCl₃) δ 2.52-2.58 (2H, m), 2.72 (3H, s), 4.39 (2H, t, J=6.0Hz), 4.65 (2H, t, J=6.9 Hz), 7.40-7.46 (2H, m), 7.57 (1H, m), 7.96-8.02(2H, m), 8.14 (1H, s), 8.71 (1H, s).

Example 1

Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminehydrochloride

4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (770 mg) and3-chloro-4-[(3-fluorobenzyl)oxy]aniline (2.52 g) were dissolved in1-methyl-2-pyrrolidone (10 mL), and the mixture was stirred with heatingat 140° C. for 2.5 hrs. After cooling to room temperature, the mixturewas diluted with ethyl acetate (300 mL), and stirred at room temperaturefor 1 hr. The precipitated powder was collected by filtration, washedwith ethyl acetate (30 mL), and dried under reduced pressure to give thetitle compound (1.62 g).

¹H-NMR (DMSO-d₆) δ: 5.27 (2H, s), 6.63 (1H, d, J=3 Hz), 7.0-7.5 (5H, m),7.78 (1H, dd, J=3 Hz, 9 Hz), 8.00 (1H, m), 8.15 (1H, d, J=3 Hz), 8.79(1H, s), 11.79 (1H, br s).

Example 2

Production of(4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}phenyl)methanol(i) Production of{4-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]phenyl}methanol

4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (307 mg) was dissolved inN,N-dimethylformamide (2 mL), potassium carbonate (304 mg) was added,and the mixture was stirred at room temperature for 30 min.4-Hydroxymethylbenzyl chloride (377 mg) was added, and the mixture wasstirred at room temperature for 16 hrs. After diluting with water (30mL), the mixture was extracted with ethyl acetate/tetrahydrofuran (3:1,80 mL×2).

The organic layer was dried over magnesium sulfate and concentratedunder reduced pressure. The residue was separated and purified by silicagel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100) togive the title compound (383 mg) as a powder.

¹H-NMR (CDCl₃) δ: 2.15 (1H, br s), 4.69 (2H, d, J=4 Hz), 5.71 (2H, s),6.76 (1H, m), 7.06 (2H, d, J=8 Hz), 7.34 (2H, d, J=8 Hz), 7.50 (1H, d,J=3 Hz), 8.69 (1H, s).

(ii) Production of(4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}phenyl)methanol

{4-[(4-Chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]phenyl}methanol(354 mg) and 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (488 mg) weredissolved in 1-methyl-2-pyrrolidone (2.58 mL), and the mixture wasstirred with heating at 140° C. for 2 hrs. After cooling to roomtemperature, the reaction mixture was diluted with ethyl acetate (80 mL)and partitioned with saturated aqueous sodium hydrogen carbonate (30mL). The organic layer was washed with saturated brine (30 mL), driedover magnesium sulfate and concentrated under reduced pressure. Theresidue was separated and purified by silica gel column chromatography(eluent, hexane:ethyl acetate=80:20→0:100) to give the title compound(588 mg) as a powder.

¹H-NMR (CDCl₃) δ: 4.77 (2H, s), 5.07 (2H, s), 5.52 (2H, s), 6.26 (2H,s), 6.64 (1H, d, J=3 Hz), 6.81 (1H, d, J=9 Hz), 6.9-7.4 (8H, m), 7.49(2H, d, J=8 Hz), 8.44 (1H, s).

Example 3

Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(3,4-dimethoxybenzoyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Under ice-cooling, to a suspension ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminehydrochloride (150 mg) and potassium carbonate (102 mg) inN,N-dimethylformamide (1.5 mL) was added 3,4-dimethoxybenzoyl chloride(82 mg), and the mixture was stirred under ice-cooling, for 1 hr. Themixture was partitioned between ethyl acetate (50 mL) and water (30 mL).The organic layer was washed with saturated brine (30 mL), dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas separated and purified by silica gel column chromatography (eluent,hexane:ethyl acetate=80:20→ethyl acetate:methanol=80:20), andcrystallized from diisopropyl ether to give the title compound (104 mg).

¹H-NMR (CDCl₃) δ: 3.97 (3H, s), 4.01 (3H, s), 5.14 (2H, s), 6.72 (1H, d,J=3 Hz), 6.9-7.6 (10H, m), 7.88 (2H, d, J=3 Hz), 8.63 (1H, s), 9.75 (1H,br s).

Example 4

Production of(4-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}phenyl)methanol

The title compound (242 mg) was obtained as crystals by the reaction inthe same manner as in Example 2 (ii) using{4-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]phenyl}methanol(200 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (235 mg) and1-methyl-2-pyrrolidone (1.46 mL).

¹H-NMR (CDCl₃) δ: 2.14 (3H, s), 2.50 (3H, s), 3.01 (1H, br s), 4.75 (2H,s), 5.53 (2H, s), 6.38 (1H, br s), 6.64 (1H, d, J=3 Hz), 6.75 (1H, d,J=9 Hz), 6.8-7.2 (6H, m), 7.34 (2H, d, J=3 Hz), 7.47 (1H, d, J=9 Hz), 809 (1H, m), 8.46 (1H, s).

Example 5

Production ofN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

The title compound (283 mg) was obtained as crystals by the reaction inthe same manner as in Example 2 (ii) using4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg),3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (418 mg) and1-methyl-2-pyrrolidone (2.6 mL).

¹H-NMR (CDCl₃) δ: 2.16 (3H, s), 2.51 (3H, s), 6.56 (1H, d, J=3 Hz), 6.80(1H, d, J=9 Hz), 7.0-7.6 (5H, m), 8 17 (1H, m), 8.59 (1H, s), 8.76 (1H,br s), 11.08 (1H, br s).

Example 6

Production of methyl4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoate(i) Production of methyl4-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoate

The title compound (1.0 g) was obtained as a powder by the reaction inthe same manner as in Example 2 (i) using4-chloro-5H-pyrrolo[3,2-d]pyrimidine (710 mg), methyl4-(bromomethyl)benzoate (1.27 g), potassium carbonate (703 mg) andN,N-dimethylformamide (9.2 mL).

¹H-NMR (CDCl₃) δ: 3.90 (3H, s), 5.77 (2H, s), 6.83 (1H, d, J=3 Hz), 7.08(2H, d, J=8 Hz), 7.53 (1H, d, J=3 Hz), 8.00 (2H, d, J=8 Hz), 8.73 (1H,s).

(ii) Production of methyl4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoate

The title compound (1.35 g) was obtained as a powder by the reaction inthe same manner as in Example 2 (ii) using methyl4-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoate (1.0 g),3-chloro-4-[(3-fluorobenzyl)oxy]aniline (1.25 g) and1-methyl-2-pyrrolidone (6.63 mL).

¹H-NMR (CDCl₃) δ: 3.93 (3H, s), 5.07 (2H, s), 5.57 (2H, s), 6.10 (2H, brs), 6.68 (1H, d, J=3 Hz), 6.7-7.4 (10H, m), 8.11 (2H, d, J=9 Hz), 8.47(1H, s).

Example 7

Production of4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoicacid

Methyl4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoate(850 mg) was dissolved in a mixed solvent of ethanol (3.29mL)/tetrahydrofuran (3.29 mL), 1N aqueous sodium hydroxide solution(3.29 mL) was added, and the mixture was stirred at room temperature for20 hrs. 1N Hydrochloric acid (3.29 mL) was added to the reaction mixtureand the mixture was diluted with water (20 mL). The precipitatedcrystals were collected by filtration, washed with water (10 mL), anddried under reduced pressure to give the title compound (738 mg).

¹H-NMR (DMSO-d₆) δ: 5.21 (2H, s), 5.94 (2H, s), 6.62 (1H, d, J=3 Hz),7.0-7.6 (9H, m), 7.84 (2H, d, J=9 Hz), 7.91 (1H, d, J=3 Hz), 8.40 (1H,s), 8.81 (1H, br s), 12.88 (1H, br s).

Example 8

Production of1-(4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoyl)piperidin-4-ol

To a mixture of4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoicacid (150 mg), 4-hydroxypiperidine (33.2 mg) and 1-hydroxybenzotriazolemonohydrate (60 mg) in N,N-dimethylformamide (3 mL) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg) andtriethylamine (0.208 mL) at room temperature and the mixture was stirredovernight at room temperature. The mixture was partitioned between ethylacetate (50 mL) and water (30 mL). The organic layer was washed withsaturated brine (30 mL), dried over magnesium sulfate, and concentratedunder reduced pressure. The residue was separated and purified by basicsilica gel column chromatography (eluent, ethylacetate:methanol=100:0→ethyl acetate:methanol=80:20), and crystallizedfrom diisopropyl ether to give the title compound (168 mg).

¹H-NMR (CDCl₃) δ: 1.4-2.1 (5H, m), 3.0-3.7 (3H, m), 3.97 (1H, m), 4.16(1H, m), 5.08 (2H, s), 5.55 (2H, s), 6.33 (1H, br s), 6.66 (1H, d, J=3Hz), 6.82 (1H, d, J=9 Hz), 6.9-7.5 (11H, m), 8.47 (1H, s).

Example 9

Production of6-(3-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production of6-chloro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-nitropyrimidin-4-aminehydrochloride

4,6-Dichloro-5-nitropyrimidine (9.7 g) was dissolved in1-methyl-2-pyrrolidone (25.7 mL), a solution of3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (5.35 g) in1-methyl-2-pyrrolidone (10 mL) was added dropwise under cooling at −15°C., and the mixture was stirred at −10° C. to 0° C. for 1 hr. Themixture was diluted with ethyl acetate (100 mL) and stirred at 0° C. for15 min. The precipitated crystals were collected by filtration, washedwith ethyl acetate (30 mL), and dried under reduced pressure to give thetitle compound (7.34 g).

¹H-NMR (DMSO-d₆) δ: 2.20 (3H, s), 2.67 (3H, s), 7.0-8.0 (5H, m), 8.44(1H, m), 8.55 (1H, s), 10.14 (1H, br s).

(ii) Production of6-chloro-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine

6-Chloro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-nitropyrimidin-4-aminehydrochloride (2.04 g) was suspended in diethyl ether (9.45 mL) and asolution of tin(IV) chloride dihydrate (9.1 g) in conc. hydrochloricacid (20.17 mL) was added under ice-cooling. After stirring at roomtemperature for 3 hrs, the reaction mixture was poured into ice water(400 mL). A 50% aqueous sodium hydroxide solution (18 mL) was addeddropwise to adjust pH to 8. Ethyl acetate (300 mL) was added and themixture was filtered through celite. The organic layer was dried overmagnesium sulfate and concentrated under reduced pressure to give thetitle compound (1.30 g).

¹H-NMR (CDCl₃) δ: 2.23 (3H, s), 2.52 (3H, s), 6.85 (1H, d, J=9 Hz),7.0-7.5 (4H, m), 8.16 (1H, s), 8.21 (1H, d, J=3 Hz).

(iii) Production of6-iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diaminehydriodide

6-Chloro-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine(400 mg) was suspended in 55% hydriodic acid (6.16 mL), sodium iodide(878 mg) was added, and the mixture was stirred with heating at 70° C.for 10 min. After cooling to room temperature, water (40 mL)/ethylacetate (30 mL) was added. After adjusting its pH to not less than 7with aqueous sodium hydrogen carbonate, and the mixture was stirred atroom temperature for 15 min. The organic layer was dried over magnesiumsulfate and concentrated under reduced pressure to give the titlecompound (626 mg).

¹H-NMR (CDCl₃) δ: 2.19 (3H, s), 2.52 (3H, s), 4.23 (2H, br s), 6.81 (1H,d, J=9 Hz), 7.0-7.5 (5H, m), 7.97 (1H, s), 8.18 (1H, d, J=3 Hz).

(iv) Production of6-[(3-aminophenyl)ethynyl]-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine

6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diaminehydriodide (200 mg) was dissolved in a mixed solvent of acetonitrile(7.6 mL)/triethylamine (5.72 mL), 3-ethynylaniline (0.0574 mL),trans-dichlorobis(triphenylphosphine)palladium(II) (15.4 mg) andcopper(I) iodide (5.3 mg) were sequentially added, and the mixture wasstirred under a nitrogen stream at room temperature for 1.5 hrs. Thereaction mixture was concentrated under reduced pressure and the residuewas separated and purified by silica gel column chromatography (eluent,hexane:ethyl acetate=80:20-4 ethyl acetate:methanol=80:20) to give thetitle compound (157 mg).

¹H-NMR (CDCl₃) δ: 2.19 (3H, s), 2.51 (3H, s), 3.65 (2H, br s), 4.37 (2H,br s), 6.6-7.5 (9H, m), 7.50 (1H, br s), 8.19 (1H, d, J=3 Hz), 8.29 (1H,s).

(v) Production of6-(3-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

6-[(3-Aminophenyl)ethynyl]-4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine(140 mg) was dissolved in N,N-dimethylformamide (0.82 mL), copper(I)iodide (6.3 mg) was added and the mixture was stirred under a nitrogenstream with heating at 110° C. for 16 hrs. After cooling to roomtemperature, the reaction mixture was diluted with dichloromethane (20mL), and filtered through celite. The filtrate was concentrated underreduced pressure, and the residue was separated and purified by basicsilica gel column chromatography (eluent, ethylacetate:methanol=100:0→85:15) and crystallized from diisopropyl ether togive the title compound (76 mg).

¹H-NMR (DMSO-d₆) δ: 2.22 (3H, s), 2.44 (3H, s), 5.32 (2H, br s), 6.65(1H, d, J=7 Hz), 6.76 (1H, d, J=2 Hz), 6.9-7.3 (6H, m), 7.75 (1H, dd,J=3 Hz, 9 Hz), 7.83 (1H, d, J=2 Hz), 8.18 (1H, d, J=3 Hz), 8.34 (1H, s),9.14 (1H, br s), 11.47 (1H, br s).

Example 10

Production of6-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production of6-[(4-aminophenyl)ethynyl]-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine

6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diaminehydriodide (270 mg) was dissolved in a mixed solvent of acetonitrile(10.3 mL)/triethylamine (7.72 mL), and 4-ethynylaniline (80.3 mg),trans-dichlorobis(triphenylphosphine)palladium(II) (20.8 mg) andcopper(I) iodide (7.16 mg) were sequentially added. The title compound(134 mg) was obtained as a powder by the reaction in the same manner asin Example 9 (iv).

¹H-NMR (CDCl₃) δ: 2.20 (3H, s), 2.51 (3H, s), 4.00 (4H, br s), 6.60 (2H,d, J=9 Hz), 6.83 (1H, d, J=9 Hz), 7.0-7.5 (6H, m), 8.21 (1H, m), 8.29(1H, s).

(ii) Production of6-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

The title compound (68 mg) was obtained as a powder by the reaction inthe same manner as in Example 9 (v) using6-[(4-aminophenyl)ethynyl]-N-4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine(160 mg) and copper(I) iodide (7.2 mg).

¹H-NMR (DMSO-d₆) δ: 2.21 (3H, s), 2.44 (3H, s), 5.58 (2H, br s), 6.70(2H, d, J=9 Hz), 6.99 (1H, d, J=2 Hz), 7.20 (2H, m), 7.56 (1H, d, J=9Hz), 7.75 (1H, dd, J=2 Hz, 9 Hz), 7.81 (1H, d, J=2 Hz), 8.18 (1H, d, J=2Hz), 8.32 (1H, s), 9.12 (1H, br s), 11.38 (1H, br s).

Example 11

Production of2-methoxy-N-{4-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]phenyl}acetamide

To a mixture of6-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(40 mg), methoxyacetic acid (0.0145 mL) and 1-hydroxybenzotriazolemonohydrate (38 mg) in N,N-dimethylformamide (1.9 mL) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54 mg) andtriethylamine (0.079 mL) at room temperature. After stirring overnightat room temperature, the reaction mixture was diluted withdichloromethane (10 mL). The residue was separated and purified by basicsilica gel column chromatography (eluent, ethylacetate:methanol=100:0→ethyl acetate:methanol=85:15) and crystallizedfrom diisopropyl ether to give the title compound (24 mg).

¹H-NMR (DMSO-d₆) δ: 2.21 (3H, s), 2.43 (3H, s), 3.39 (3H, s) 4.04 (2H,s), 6.91 (1H, d, J=2 Hz), 6.99 (1H, d, J=9 Hz), 7.20 (2H, m), 7.7-7.9(6H, m), 8.17 (1H, d, J=3 Hz), 8.33 (1H, s), 9.07 (1H, br s), 9.97 (1H,br s), 11.52 (1H, br s).

Example 12

Production of6-(4-methoxyphenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminehydrochloride (i) Production of6-(4-methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ol

Ethyl 3-amino-5-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (7.2 g) wasdissolved in tetrahydrofuran (16 mL)/ethanol (32 mL), formamidine (3.46g) was added, and the mixture was stirred at 90° C. for 16 hrs. Aftercooling to room temperature, tetrahydrofuran was evaporated underreduced pressure. The residue was diluted with ethanol (20 mL), and theprecipitated powder was collected by filtration, washed with ethanol (15mL) and dried under reduced pressure to give the title compound (769mg).

¹H-NMR (DMSO-d₆) δ: 3.80 (3H, s), 6.76 (1H, s), 6.9-7.1 (3H, m) 7.7-8.0(2H, m), 11.83 (1H, br s).

(ii) Production of4-chloro-6-(4-methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidine

6-(4-Methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ol (500 mg) wassuspended in N,N-diethylaniline (1.11 mL)/1,2-dichloroethane (3.73 mL),phosphorus oxychloride (2.29 mL) was added, and the mixture was stirredwith heating at 110° C. for 2 hrs. After cooling to room temperature,the reaction mixture was treated with ice water (20 mL), and adjusted topH 7 or above with aqueous ammonia. After diluting with tetrahydrofuran(500 mL), the mixture was washed with saturated brine (50 mL). Theorganic layer was dried over magnesium sulfate and concentrated underreduced pressure. The residue was separated and purified by silica gelcolumn chromatography (eluent, hexane:ethyl acetate=80:20→20:80) to givethe title compound (25 mg).

¹H-NMR (CDCl₃) δ: 3.90 (3H, s), 6.92 (1H, s), 7.05 (2H, d, J=9 Hz), 7.71(2H, d, J=9 Hz), 8.73 (1H, s).

(iii) Production of6-(4-methoxyphenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminehydrochloride

The title compound (11 mg) was obtained as crystals by the reaction inthe same manner as in Example 1 using4-chloro-6-(4-methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidine (13 mg),3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (16 mg) and1-methyl-2-pyrrolidone (0.2 mL).

¹H-NMR (DMSO-d₆) δ: 2.24 (3H, s), 2.46 (3H, s), 3.86 (3H, s), 7.02 (1H,s), 7.14 (2H, d, J=9 Hz), 7.26 (2H, m), 7.80 (1H, dd, J=3 Hz, 9 Hz),7.90 (1H, d, J=3 Hz), 8.11 (2H, d, J=9 Hz), 8.22 (1H, d, J=3 Hz), 8.72(1H, s), 11.54 (1H, br s).

Example 13

Production of(2E)-3-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]-2-propen-1-ol(i) Production of(2E)-5-[5-amino-6-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)pyrimidin-4-yl]-2-penten-4-yn-1-ol

6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diaminehydriodide (507 mg) was dissolved in a mixed solvent of acetonitrile(19.4 mL)/triethylamine (14.5 mL), 2-penten-4-yn-1-ol (106 mg),trans-dichlorobis(triphenylphosphine)palladium(II) (38.8 mg) andcopper(I) iodide (13.4 mg) were sequentially added. The title compound(373 mg) was obtained as a powder by the reaction in the same manner asin Example 9 (iv).

¹H-NMR (DMSO-d₆) δ: 2.17 (3H, s), 2.43 (3H, s), 4.12 (2H, m), 5.52 (2H,br s), 6.05 (1H, dt, J=2 Hz, 16 Hz), 6.53 (1H, dt, J=5 Hz, 16 Hz), 6.93(1H, d, J=9 Hz), 7.20 (2H, m), 7.63 (2H, m), 7.96 (1H, s), 8.15 (1H, d,J=3 Hz), 8.57 (1H, br s).

(ii) Production of (2E)-3-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]-2-propen-1-ol

The title compound (59 mg) was obtained by the reaction in the samemanner as in Example 9 (v) using(2E)-5-[5-amino-6-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)pyrimidin-4-yl]-2-penten-4-yn-1-ol (200 mg), copper(I)iodide (9.8 mg) and N,N-dimethylformamide (1.29 mL), and crystallizationfrom diisopropyl ether.

¹H-NMR (DMSO-d₆) δ: 2.20 (3H, s), 2.43 (3H, s), 4.22 (2H, d, J=3 Hz),6.45 (1H, m), 6.50 (1H, s), 6.67 (1H, dt, J=16 Hz), 6.98 (1H, d, J=9Hz), 7.19 (2H, m), 7.72 (1H, dd, J=3 Hz, 9 Hz), 7.80 (1H, d, J=2 Hz),8.17 (1H, d, J=2 Hz), 8.30 (1H, s), 9.02 (1H, br s), 11.30 (1H, br s).

Example 14

Production of6-[3-(aminomethyl)phenyl]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production of tert-butyl3-{[5-amino-6-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)pyrimidin-4-yl]ethynyl}benzylcarbamate

6-Iodo-N-4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diaminehydriodide (500 mg) was dissolved in a mixed solvent of acetonitrile(14.8 mL)/triethylamine (11.0 mL), and tert-butyl3-ethynylbenzylcarbamate (247 mg),trans-dichlorobis(triphenylphosphine)palladium(II) (31.3 mg) andcopper(I) iodide (10.2 mg) were sequentially added. The title compound(376 mg) was obtained as a powder by the reaction in the same manner asin Example 9 (iv).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.24 (3H, s), 2.53 (3H, s), 4.00 (2H, brs), 4.32 (2H, d, J=6 Hz), 5.04 (1H, br s), 6.87 (1H, d, J=9 Hz), 7.01(1H, br s), 7.09-7.5 (9H, m), 8.22 (1H, d, J=2 Hz), 8.34 (1H, s).

(ii) Production of tert-butyl3-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]benzylcarbamate

The title compound (287 mg) was obtained as a powder by the reaction inthe same manner as in Example 9 (v) using tert-butyl3-{[5-amino-6-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)pyrimidin-4-yl]ethynyl}benzylcarbamate(363 mg) and copper(I) iodide (12.9 mg).

¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 2.17 (3H, s), 2.51 (3H, s) 4.23 (2H, brs), 5.67 (1H, br s), 6.72 (1H, s), 6.82 (1H, d, J=8 Hz), 6.9-7.7 (8H,m), 8.16 (1H, br s), 8.60 (1H, s), 8.66 (1H, br s), 10.64 (1H, br s).

(iii) Production of6-[3-(aminomethyl)phenyl]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

tert-Butyl3-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]benzylcarbamate(230 mg) was suspended in tetrahydrofuran (2.3 mL), 2N hydrochloric acid(2.3 mL) was added, and the mixture was stirred with heating at 60° C.for 3 hrs. After cooling to room temperature, 1N aqueous sodiumhydroxide solution (4.6 mL) was added, and the mixture was stirred atroom temperature for 5 min. The solvent was removed by decantation, andthe residue was dissolved in tetrahydrofuran (30 mL), dried overpotassium carbonate, and concentrated under reduced pressure. Theresidue was triturated with diisopropyl ether, collected by filtrationand dried under reduced pressure to give the title compound (164 mg).

¹H-NMR (DMSO-d₆) δ: 2.18 (3H, s), 2.41 (3H, s), 3.92 (2H, br s), 4.86(2H, br s), 6.9-8.2 (11H, m), 8.33 (1H, s), 9.62 (1H, br s), 12.13 (1H,br s).

Example 15

Production of2-methoxy-N-{3-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]benzyl}acetamide

The title compound (56 mg) was obtained by the reaction in the samemanner as in Example 11 using6-[3-(aminomethyl)phenyl]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(50 mg), methoxyacetic acid (0.01055 mL), 1-hydroxybenzotriazolemonohydrate (23.2 mg), N,N-dimethylformamide (2.3 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (32.9 mg)and triethylamine (0.080 mL).

¹H-NMR (DMSO-d₆) δ: 2.27 (3H, s), 2.52 (3H, s), 3.44 (3H, s), 3.98 (2H,s), 4.56 (2H, d, J=6 Hz), 6.65 (1H, s), 6.82 (1H, d, J=2 Hz), 6.93 (1H,d, J=8 Hz), 7.11 (2H, m), 7.3-7.9 (6H, m), 8.22 (1H, m), 8.47 (1H, s),8.82 (1H, br s), 11.26 (1H, br s).

Example 16

Production of6-(aminomethyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production of tert-butyl3-[5-amino-6-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)pyrimidin-4-yl]-2-propynylcarbamate

6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diaminehydriodide (500 mg) was dissolved in a mixed solvent of acetonitrile(14.8 mL)/triethylamine (11.0 mL), and tert-butyl 2-propynylcarbamate(166 mg), trans-dichlorobis(triphenylphosphine)palladium(II) (31.3 mg)and copper(I) iodide (10.2 mg) were sequentially added. The titlecompound (303 mg) was obtained as a powder by the reaction in the samemanner as in Example 9 (iv).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.22 (3H, s), 2.52 (3H, s), 4.06 (2H, brs), 4.17 (2H, d, J=6 Hz), 5.09 (1H, br s), 6.84 (1H, d, J=9 Hz), 7.0-7.5(4H, m), 8.20 (1H, d, J=3 Hz), 8.25 (1H, s).

(ii) Production of tert-butyl[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]methylcarbamate

The title compound (212 mg) was obtained as a powder by the reaction inthe same manner as in Example 9 (v) using tert-butyl3-[5-amino-6-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)pyrimidin-4-yl]-2-propynylcarbamate(286 mg) and copper(I) iodide (11.8 mg).

¹H-NMR (CDCl₃) δ: 1.38 (9H, s), 2.20 (3H, s), 2.52 (3H, s), 4.30 (2H, d,J=6 Hz), 5.38 (1H, t, J=6 Hz), 6.32 (1H, br s), 6.83 (1H, d, J=9 Hz),7.07 (1H, d, J=9 Hz), 7.1-7.4 (4H, m), 7.84 (1H, br s), 8.20 (1H, d, J=2Hz), 8.50 (1H, s), 9.95 (1H, br s).

(iii) Production of6-(aminomethyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

The title compound (160 mg) was obtained as a powder by the reaction inthe same manner as in Example 14 (iii) using tert-butyl[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]melhylcarbamate(165 mg), 2N hydrochloric acid (1.92 mL) and tetrahydrofuran (1.92 mL).

¹H-NMR. (DMSO-d₆) δ: 2.17 (3H, s), 2.42 (3H, s), 3.59 (2H, t, J=6 Hz),3.95 (2H, s), 6.25 (1H, s), 6.86 (1H, s), 6.94 (1H, d, J=8 Hz), 7.1-7.3(2H, m), 7.78 (2H, m), 8.14 (1H, d, J=3 Hz), 8.26 (1H, s), 9.46 (1H, brs), 11.50 (1H, br s).

Example 17

Production of(2E)-4-(dimethylamino)-N-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]methyl}-2-butenamide

The title compound (32 mg) was obtained by the reaction in the samemanner as in Example 11 using6-(aminomethyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(40 mg), (2E)-4-(dimethylamino)-2-butenoic acid hydrochloride (22 mg),1-hydroxybenzotriazole monohydrate (22.5 mg), N,N-dimethylformamide (2.2mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (31.9mg) and triethylamine (0.0928 mL).

¹H-NMR (DMSO-d₆) δ: 2.15 (6H, s), 2.19 (3H, s), 2.43 (3H, s), 3.01 (2H,d, J=5 Hz), 4.55 (2H, d, J=5 Hz), 6.12 (1H, d, J=16 Hz), 6.36 (1H, d,J=1 Hz), 6.68 (1H, m), 6.96 (1H, d, J=8 Hz), 7.18 (2H, m), 7.74 (2H, m),8.16 (1H, d, J=3 Hz), 8.30 (1H, s), 8.70 (1H, t, J=5 Hz), 9.30 (1H, brs), 11.03 (1H, br s).

Example 18

Production of6-[(1E)-3-amino-1-propen-1-yl]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production of tert-butyl(2E)-5-[5-amino-6-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)pyrimidin-4-yl]-2-penten-4-yn-1-ylcarbamate

6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diaminehydriodide (500 mg) was dissolved in a mixed solvent of acetonitrile(14.8 mL)/triethylamine (11.0 mL), and tert-butyl(2E)-2-penten-4-yn-1-ylcarbamate (194 mg),trans-dichlorobis(triphenylphosphine)palladium(II) (31.3 mg) andcopper(I) iodide (10.2 mg) were sequentially added. The title compound(199 mg) was obtained as a powder by the reaction in the same manner asin Example 9 (iv).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.20 (3H, s), 2.52 (3H, s), 3.85 (2H,m), 4.22 (2H, br s), 5.02 (1H, br s), 5.84 (1H, d, J=16 Hz), 6.29 (1H,m), 6.84 (1H, d, J=9 Hz), 7.0-7.5 (5H, m), 8.19 (1H, d, J=2 Hz), 8.26(1H, s).

(ii) Production of tert-butyl(2E)-3-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]-2-propenylcarbamate

The title compound (66 mg) was obtained as a powder by the reaction inthe same manner as in Example 9 (v) using tert-butyl(2E)-5-[5-amino-6-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)pyrimidin-4-yl]-2-penten-4-yn-1-ylcarbamate(195 mg) and copper(I) iodide (7.63 mg).

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 2.12 (3H, s), 2.49 (3H, s) 3.82 (2H, brs), 5.53 (1H, br s), 6.00 (1H, d, J=16 Hz), 6.36 (1H, m), 6.77 (1H, d,J=9 Hz), 7.0-7.5 (4H, m), 8.09 (1H, s), 8.43 (1H, br s), 8.51 (1H, brs), 11.00 (1H, br s).

(iii) Production of6-[(1E)-3-amino-1-propen-1-yl]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

The title compound (41 mg) was obtained as a powder by the reaction inthe same manner as in Example 14 (iii) using tert-butyl(2E)-3-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]-2-propenylcarbamate(65 mg), 2N hydrochloric acid (0.755 mL) and tetrahydrofuran (0.755 mL).

¹H-NMR (DMSO-d₆) δ: 2.17 (3H, s), 2.42 (3H, s), 3.41 (2H, m), 6.40 (1H,s), 6.62 (2H, m), 6.96 (1H, d, J=8 Hz), 7.17 (2H, m), 7.95 (2H, m), 8.16(1H, d, J=3 Hz), 8.28 (1H, s), 10.09 (1H, br s), 12.43 (1H, br s).

Example 19

Production of2-methoxy-N-{(2E)-3-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]-2-propenyl}acetamide

The title compound (15 mg) was obtained by the reaction in the samemanner as in Example 11 using6-[(1E)-3-aminopropen-1-yl]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(50 mg), methoxyacetic acid (0.0119 mL), 1-hydroxybenzotriazolemonohydrate (26.2 mg), N,N-dimethylformamide (2.56 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (37.2 mg)and triethylamine (0.090 mL).

¹H-NMR (DMSO-d₆) δ: 2.20 (3H, s), 2.43 (3H, s), 3.36 (3H, s), 3.88 (2H,s), 3.97 (2H, t, J=5 Hz), 6.32 (1H, m), 6.49 (1H, d, J=1 Hz), 6.56 (1H,d, J=17 Hz), 6.97 (1H, d, J=9 Hz), 7.19 (2H, m), 7.75 (2H, m), 8.15 (1H,d, J=2 Hz), 8.24 (1H, t, J=5 Hz), 8.29 (1H, s), 9.04 (1H, br s), 11.33(1H, br s).

Example 20

Production of(2E)-3-[5-ethyl-4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]-2-propen-1-ol(i) Production of 4-iodo-6-phenoxypyrimidin-5-amine

4,6-Diiodopyrimidin-5-amine (2.2 g) was dissolved in1-methyl-2-pyrrolidone (11.5 mL), phenol (656 mg) and potassiumcarbonate (964 mg) were added, and the mixture was stirred at 100° C.for 16 hrs. After cooling to room temperature, the mixture was dilutedwith ethyl acetate (200 mL) and washed successively with water (100 mL)and saturated brine (100 mL).

The organic layer was dried over magnesium sulfate and concentratedunder reduced pressure. The residue was separated and purified by silicagel column chromatography (eluent, hexane:ethyl acetate=80:20→20:80) togive the title compound (2.0 g) as an oil.

¹H-NMR (CDCl₃) δ: 4.34 (2H, br s), 7.1-7.5 (5H, m), 7.87 (1H, s).

(ii) Production of4-((3E)-5-{[tert-butyl(dimethyl)silyl]oxy}-3-penten-1-ynyl)-6-phenoxypyrimidin-5-amine

4-Iodo-6-phenoxypyrimidin-5-amine (1.0 g) was dissolved in a mixedsolvent of acetonitrile (53 mL)/triethylamine (39 mL), andtert-butyl(dimethyl)[(2E)-2-penten-4-ynyloxy]silane (753 mg),trans-dichlorobis(triphenylphosphine)palladium(II) (112 mg) andcopper(I) iodide (36.5 mg) were sequentially added. The title compound(1.07 g) was obtained as crystals by the reaction in the same manner asin Example 9 (iv).

¹H-NMR (CDCl₃) δ: 0.09 (6H, s), 0.93 (9H, s), 4.32 (2H, m), 4.42 (2H, brs), 6.08 (1H, dt, J=16 Hz, 3 Hz), 6.48 (1H, dt, J=16 Hz, 4 Hz), 7.1-7.5(5H, m), 8.11 (1H, s).

(iii) Production of6-((1E)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-propenyl)-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine

The title compound (409 mg) was obtained as a powder by the reaction inthe same manner as in Example 9 (v) using4-((3E)-5-{[tert-butyl(dimethyl)silyl]oxy}-3-penten-1-ynyl)-6-phenoxypyrimidin-5-amine(950 mg) and copper(I) iodide (47.4 mg).

¹H-NMR (CDCl₃) δ: 0.12 (6H, s), 0.95 (9H, s), 4.39 (2H, m), 6.44 (1H,dt, J=16 Hz, 4 Hz), 6.67 (2H, m), 7.1-7.5 (5H, m), 8.48 (1H, s), 9.07(1H, br s).

(iv) Production of6-((1E)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-propenyl)-5-ethyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine

6-((1E)-3-{[tert-Butyl(dimethyl)silyl]oxy}-1-propenyl)-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine(100 mg) was dissolved in N,N-dimethylformamide (0.786 mL), cesiumcarbonate (102.6 mg) was added, and the mixture was stirred at roomtemperature for 20 min. Iodoethane (0.0231 mL) was added and the mixturewas stirred at room temperature for 2 hrs and at 40° C. for 4 hrs. Aftercooling to room temperature, the reaction mixture was diluted with ethylacetate (50 mL) and washed successively with water (30 mL) and saturatedbrine (30 mL). The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure. The residue was separated andpurified by silica gel column chromatography (eluent, hexane:ethylacetate=80:20→50:50) to give the title compound (79 mg) as an oil.

¹H-NMR (CDCl₃) δ: 0.14 (6H, s), 0.97 (9H, s), 1.44 (3H, t, J=7 Hz), 4.44(2H, m), 4.52 (2H, q, J=7 Hz), 6.58 (1H, dt, J=15 Hz, 4 Hz), 6.74 (1H,s), 6.78 (1H, m), 7.2-7.5 (5H, m), 8.41 (1H, s).

(v) Production of(2E)-3-[5-ethyl-4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]-2-propen-1-ol

A mixture of6-((1E)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-propenyl)-5-ethyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine(78 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (61.2 mg),pyridine hydrochloride (26 mg) and phenol (122 mg) was stirred withheating at 120° C. for 16 hrs. After cooling to room temperature, themixture was diluted with dichloromethane (30 mL), and washed withsaturated aqueous sodium hydrogen carbonate (20 mL). The organic layerwas dried over magnesium sulfate and concentrated under reducedpressure. The residue was separated and purified by basic silica gelcolumn chromatography (eluent, ethyl acetate:methanol=100:0→80:20) togive the title compound (32 mg) as a powder.

¹H-NMR (CDCl₃) δ: 1.46 (3H, t, J=7 Hz), 2.24 (3H, s), 2.53 (3H, s), 4.31(2H, q, J=7 Hz), 4.42 (1H, dd, J=5 Hz, 2 Hz), 6.54 (1H, dt, J=15 Hz, 5Hz), 6.66 (1H, s), 6.70 (1H, d, J=15 Hz), 6.88 (1H, d, J=8 Hz), 7.0-7.4(4H, m), 8.20 (1H, d, J=2 Hz), 8.46 (1H, s).

Example 21

Production of[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]methanolhydrochloride (i) Production of3-(5-amino-6-phenoxypyrimidin-4-yl)-2-propyn-1-ol

4-Iodo-6-phenoxypyrimidin-5-amine (3.0 g) was dissolved in a mixedsolvent of acetonitrile (159 mL)/triethylamine (117 mL), and2-propyn-1-ol (0.669 mL),trans-dichlorobis(triphenylphosphine)palladium(II) (336 mg) andcopper(I) iodide (109.5 mg) were sequentially added. The title compound(2.02 g) was obtained as crystals by the reaction in the same manner asin Example 9 (iv).

¹H-NMR (CDCl₃) δ: 3.53 (1H, br s), 4.52 (2H, br s), 4.63 (2H, br s),7.1-7.5 (5H, m), 8.09 (1H, s).

(ii) Production of (4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanol

The title compound (1.31 g) was obtained as crystals by the reaction inthe same manner as in Example 9 (v) using3-(5-amino-6-phenoxypyrimidin-4-yl)-2-propyn-1-ol (1.98 g) and copper(I)iodide (156 mg).

¹H-NMR (DMSO-d₆) δ: 4.67 (2H, d, J=5 Hz), 5.45 (1H, t, J=5 Hz), 6.50(1H, s), 7.2-7.5 (5H, m), 8.26 (1H, s), 12.15 (1H, br s).

(iii) Production of[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]methanolhydrochloride

The title compound (142 mg) was obtained as crystals by the reaction inthe same manner as in Example 1 using(4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanol (100 mg),3-chloro-4-[(3-fluorobenzyl)oxy]aniline (156 mg), pyridine hydrochloride(56.7 mg) and 1-methyl-2-pyrrolidone (0.828 mL).

¹H-NMR (DMSO-d₆) δ: 4.76 (2H, s), 5.27 (2H, s), 6.50 (1H, d, J=2 Hz),7.1-7.6 (5H, m), 7.73 (1H, dd, J=3 Hz, 9 Hz), 8.12 (1H, d, J=3 Hz), 8.77(1H, s), 11.50 (1H, br s).

Example 22

Production of(2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl]-2-propen-1-ol (i) Production of(2E)-5-(5-amino-6-phenoxypyrimidin-4-yl)-2-penten-4-yn-1-ol

4-Iodo-6-phenoxypyrimidin-5-amine (3.5 g) was dissolved in a mixedsolvent of acetonitrile (185 mL)/triethylamine (136 mL), and2-penten-4-yn-1-ol (1.1 g),trans-dichlorobis(triphenylphosphine)palladium(II) (392 mg) andcopper(I) iodide (127 mg) were sequentially added. The title compound(1.79 g) was obtained as a powder by the reaction in the same manner asin Example 9 (iv).

¹H-NMR (CDCl₃) δ: 2.48 (1H, br s), 4.33 (2H, dd, J=5 Hz, 2 Hz), 4.45(2H, br s), 6.12 (1H, dt, J=2 Hz, 16 Hz), 6.54 (1H, dt, J=16 Hz, 5 Hz),7.1-7.5 (5H, m), 8.11 (1H, s).

(ii) Production of(2E)-3-(4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propen-1-ol

The title compound (1.25 g) was obtained as crystals by the reaction inthe same manner as in Example 9 (v) using(2E)-5-(5-amino-6-phenoxypyrimidin-4-yl)-2-penten-4-yn-1-ol (1.7 g) andcopper(I) iodide (268 mg).

¹H-NMR (CDCl₃) δ: 2.38 (1H, br s), 4.41 (2H, d, J=4 Hz), 6.58 (1H, dt,J=3 Hz, 16 Hz), 6.66 (1H, s), 6.75 (1H, d, J=16 Hz), 7.2-7.5 (5H, m),8.48 (1H, s), 9.73 (1H, br s).

(iii) Production of(2E)-3-(4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propenyl benzoate

(2E)-3-(4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propen-1-ol (1.0 g)was suspended in tetrahydrofuran (20 mL), and triethylamine (0.651 mL)and benzoyl chloride (0.86 mL) were sequentially added underice-cooling. The mixture was stirred under ice-cooling for 2 hrs,diluted with ethyl acetate (200 mL) and washed with water (50 mL). Theorganic layer was dried over magnesium sulfate and concentrated underreduced pressure. The residue was separated and purified by basic silicagel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100) togive the title compound (1.08 g) as crystals.

¹H-NMR (CDCl₃) δ: 5.03 (2H, d, J=6 Hz), 6.52 (1H, m), 6.72 (1H, dt, J=16Hz, 2 Hz), 6.80 (1H, d, J=16 Hz), 7.1-7.7 (8H, m), 8.08 (2H, m), 8.50(1H, s), 9.27 (1H, br s).

(iv) Production of(2E)-3-(5-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propenylbenzoate

(2E)-3-(4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propenyl benzoate(500 mg) was dissolved in N,N-dimethylformamide (4 mL), and potassiumcarbonate (279 mg) and iodomethane (0.1 mL) were sequentially added.After stirring at room temperature for 4 hrs, water (30 mL) was added tothe reaction mixture and the mixture was extracted with ethyl acetate(100 mL), dried over magnesium sulfate and concentrated under reducedpressure. The residue was separated and purified by basic silica gelcolumn chromatography (eluent, hexane:ethyl acetate=80:20→50:50) to givethe title compound (301 mg) as crystals.

¹H-NMR (CDCl₃) δ: 4.14 (3H, s), 5.08 (2H, dd, J=6 Hz, 1 Hz), 6.66 (1H,m), 6.84 (1H, s), 6.85 (1H, d, J=16 Hz), 7.2-7.7 (8H, m), 8.10 (2H, d,J=9 Hz), 8.42 (1H, s).

(v) Production of(2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl]-2-propen-1-ol

A mixture of(2E)-3-(5-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propenylbenzoate (100 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (130 mg),pyridine hydrochloride (36 mg) and 1-methyl-2-pyrrolidone (0.518 mL) wasstirred with heating at 140° C. for 4 hrs. After cooling to roomtemperature, aqueous sodium hydrogen carbonate (20 mL) was added to thereaction mixture and the mixture was extracted with ethyl acetate (100mL). The organic layer was dried over magnesium sulfate and concentratedunder reduced pressure. The residue was dissolved in tetrahydrofuran(0.518 mL)/ethanol (0.518 mL), 1N aqueous sodium hydroxide solution(0.518 mL) was added, and the mixture was stirred at room temperaturefor 2 hrs. Tetrahydrofuran/ethyl acetate (1:1, 50 mL) and saturatedbrine (30 mL) were added, and the mixture was extracted. The organiclayer was dried over magnesium sulfate and concentrated under reducedpressure. The residue was separated and purified by basic silica gelcolumn chromatography (eluent, ethyl acetate:methanol=100:0→85:15) togive the title compound (45 mg) as crystals.

¹H-NMR (DMSO-d₆) δ: 4.00 (3H, s), 4.21 (2H, t, J=4 Hz), 5.07 (1H, t, J=5Hz), 5.23 (2H, s), 6.58 (1H, m), 6.68 (1H, s), 6.80 (1H, d, J=16 Hz),7.1-7.8 (7H, m), 8.21 (1H, s), 8.49 (1H, br s).

Example 23

Production of(2E)-3-[5-methyl-4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]-2-propen-1-ol

The title compound (60 mg) was obtained as crystals by the reaction inthe same manner as in Example 22 (v) using(2E)-3-(5-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propenylbenzoate (100 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (111mg), pyridine hydrochloride (36 mg) and 1-methyl-2-pyrrolidone (0.518mL).

¹H-NMR (DMSO-d₆) δ: 2.16 (3H, s), 2.43 (3H, s), 4.02 (3H, s) 4.22 (2H,br s), 5.07 (1H, t, J=5 Hz), 6.60 (1H, m), 6.69 (1H, s), 6.80 (1H, d,J=16 Hz), 6.93 (1H, d, J=9 Hz), 7.1-7.6 (5H, m), 8.16 (1H, d, J=2 Hz),8.23 (1H, s), 8.54 (1H, br s).

Example 24

Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-[(3,4-dimethoxyphenyl)sulfonyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine

N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminehydrochloride (150 mg) was dissolved in N,N-dimethylformamide (1.5 mL),and potassium carbonate (102 mg) and (3,4-dimethoxyphenyl)sulfonylchloride (96.9 mg) were sequentially added under ice-cooling. Themixture was stirred under ice-cooling for 2 hrs, and at room temperaturefor 1 hr. The mixture was diluted with ethyl acetate (50 mL) and washedtwice with water (30 mL). The organic layer was dried over magnesiumsulfate and concentrated under reduced pressure. The residue wasseparated and purified by silica gel column chromatography (eluent,hexane:ethyl acetate=80:20→0:100) to give the title compound (95 mg) asa powder.

¹H-NMR (CDCl₃) δ: 3.68 (3H, s), 3.86 (3H, s), 5.16 (2H, s), 6.76 (1H, d,J=4 Hz), 6.82 (1H, d, J=9 Hz), 6.97 (1H, d, J=9 Hz), 7.02 (1H, m),7.1-7.4 (5H, m), 7.55 (1H, dd, J=9 Hz. 3 Hz), 7.79 (1H, d, J=4 Hz), 7.94(1H, d, J=3 Hz), 8.52 (1H, s), 9.39 (1H, br s).

Example 25

Production of ethyl5-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-2-furoate(i) Production of ethyl5-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]-2-furoate

To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg) inN,N-dimethylformamide (6.5 mL) was added potassium carbonate (541 mg)under ice-cooling, and the mixture was stirred for 15 min. while warmingto room temperature. Ethyl 5-(chloromethyl)-2-furoate (737 mg) was addedto the reaction mixture, and the mixture was stirred at room temperaturefor 16 hrs. The reaction mixture was diluted with water (20 mL), andextracted with a mixed solvent (40 mL×3) of ethylacetate/tetrahydrofuran (1/1). The organic layer was washed withsaturated brine (20 mL×3) and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the obtainedresidue was subjected to silica gel column chromatography (silica gel,eluent:hexane/ethyl acetate=80/20→10/90). The object fraction wasconcentrated under reduced pressure and dried to give the title compound(825 mg) as a pale-yellow solid.

¹H-NMR (CDCl₃) δ 1.37 (3H, t, J=7.2 Hz), 4.36 (2H, q, J=7.2 Hz), 5.75(2H, s), 6.30 (1H, ddd, J=0.9, 2.1, 2.7 Hz), 6.80 (1H, t, J=3.9 Hz),7.10 (1H, t, J=3.3 Hz), 7.63 (1H, dd, J=2.7, 3.3 Hz), 8.73 (1H, d, J=3.9Hz).

(ii) Production of ethyl5-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-2-furoate

To a solution of ethyl5-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]-2-furoate (200 mg)in 1-methyl-2-pyrrolidone (1.3 mL) was added3-chloro-4-[(3-fluorobenzyl)oxy]aniline (247 mg), and the mixture washeated to 140° C. and stirred for 2 hrs. The reaction mixture wasallowed to cool to room temperature, diluted with 5% aqueous sodiumhydrogen carbonate solution (20 mL) and extracted with ethyl acetate (20mL×3). The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the obtained residue was subjected to silica gel columnchromatography (silica gel, eluent:ethyl acetate/methanol=10/0→8/2). Theobject fraction was concentrated under reduced pressure and dried togive the title compound (307 mg) as a pale-yellow solid.

¹H-NMR (CDCl₃) δ 1.34 (3H, t, J=7.2 Hz), 4.38 (2H, q, J=7.2 Hz), 5.14(2H, s), 5.49 (2H, s), 6.45 (1H, d, J=3.4 Hz), 6.63 (1H, d, J=3.0 Hz),6.94 (1H, d, J=8.8 Hz), 7.03 (1H, d, J=9.6 Hz), 7.26-7.38 (6H, m), 7.43(1H, dd, J=2.6, 8.8 Hz), 7.65 (1H, d, J=3.0 Hz), 8.50 (1H, s).

Example 26

Production of5-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-2-furancarboxylicacid

To a solution of ethyl5-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-2-furoate(280 mg) in a mixed solvent of tetrahydrofuran (1.34 mL) and ethanol(1.34 mL) was added 1N aqueous sodium hydroxide solution (1.34 mL) andthe mixture was stirred at room temperature for 14 hrs. 1N Hydrochloricacid (1.34 mL) and water (10 mL) were added to the reaction mixture andthe mixture was stirred at room temperature for 30 min. The resultantprecipitate was collected by filtration, washed with water (10 mL×3) anddiisopropyl ether (10 mL×3) and dried under reduced pressure (80° C.) togive the title compound (178 mg) as a white powder.

¹H-NMR (DMSO-d₆) δ 5.24 (2H, s), 5.89 (2H, s), 6.37 (1H, d, J=3.3 Hz),6.54 (1H, d, J=2.7 Hz), 7.10 (1H, d, J=3.3 Hz), 7.21 (2H, d, J=9.0 Hz),7.32 (2H, t, J=6.6 Hz), 7.48 (2H, t, J=8.1 Hz), 7.73 (2H, d, J=9.6 Hz),8.29 (1H, s), 8.57 (1H, br s).

Example 27

Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-{4-[(cis-3,5-dimethylpiperazin-1-yl)carbonyl]benzyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a solution of4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoicacid (120 mg) in N,N-dimethylformamide (2.4 mL) were addedcis-2,6-dimethylpiperazine (95 mg) and 1H-1,2,3-benzotriazol-1-ol (65mg), and the mixture was stirred at room temperature for 15 min.N-[3-(Dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (92 mg)and triethylamine (0.2 mL) were added, and the mixture was stirred atroom temperature for 12 hrs. The reaction mixture was diluted with water(20 mL) and extracted with ethyl acetate (25 mL×3). The organic layerwas washed with saturated brine (20 mL×3) and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the obtained residue was subjected to silica gel columnchromatography (basic silica gel, eluent:ethylacetate/methanol=10/0→9/1). The object fraction was concentrated underreduced pressure. Chloroform/diisopropyl ether (3/7) was added to theresidue and the resultant precipitate was collected by filtration anddried under reduced pressure to give the title compound (85 mg) as whitepowder crystals.

¹H-NMR (CDCl₃) δ 1.13 (6H, d, J=6.6 Hz), 1.66 (4H, br s), 2.69 (2H, br),3.41 (1H, brd, J=6.6 Hz), 4.60 (1H, brd, J=13.5 Hz), 5.08 (2H, s), 5.56(2H, s), 6.28 (1H, s), 6.68 (1H, dd, J=2.1, 5.4 Hz), 6.82 (1H, d, J=9.3Hz), 7.00 (2H, dt, J=2.1, 8.7 Hz), 7.15-7.21 (4H, m), 7.25 (1H, d, J=2.4Hz), 7.30-7.38 (4H, m), 7.48 (2H, d, J=8.4 Hz), 8.48 (1H, s).

Example 28

Production ofN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (63 mg) in1-methyl-2-pyrrolidone (0.8 mL), was added3-chloro-4-(pyridin-2-ylmethoxy)aniline (149 mg), and the mixture washeated to 140° C. and stirred for 2 hrs. The reaction mixture wasallowed to cool to room temperature, diluted with 5% aqueous sodiumhydrogen carbonate solution (20 mL) and extracted with a mixed solvent(25 mL×3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the obtainedresidue was subjected to silica gel column chromatography (basic silicagel, eluent:ethyl acetate/methanol=10/0→8/2). The object fraction wasconcentrated under reduced pressure. Chloroform/diisopropyl ether (1/9)was added to the residue, and the resultant precipitate was collected byfiltration and dried under reduced pressure to give the title compound(112 mg) as pale-yellow powder crystals.

¹H-NMR (DMSO-d₆) δ 5.27 (2H, s), 6.48 (1H, d, J=2.4 Hz), 7.25 (1H, d,J=8.7 Hz), 7.37 (1H, dd, J=5.1, 7.5 Hz), 7.55-7.60 (2H, m), 7.66 (1H,s), 7.89 (1H, t, J=7.5 Hz), 8.20 (1H, dd, J=1.5, 2.4 Hz), 8.35 (1H, d,J=1.5 Hz), 8.60 (1H, dd, J=0.6, 4.8 Hz), 9.25 (1H, s), 12.78 (1H, s).

Example 29

Production of ethyl5-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]-2-furoate

To a solution of ethyl5-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]-2-furoate (300 mg)in 1-methyl-2-pyrrolidone (2.0 mL) was added3-chloro-4-(pyridin-2-ylmethoxy)aniline (360 mg), and the mixture washeated to 140° C. and stirred for 1.5 hrs. The reaction mixture wasallowed to cool to room temperature, diluted with 5% aqueous sodiumhydrogen carbonate solution (30 mL) and extracted with a mixed solvent(45 mL×3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the obtainedresidue was subjected to silica gel column chromatography (basic silicagel, eluent:ethyl acetate/methanol=10/0→8/2). The object fraction wasconcentrated under reduced pressure. Chloroform/diisopropyl ether (1/9)was added to the residue, and the resultant precipitate was collected byfiltration and dried under reduced pressure to give the title compound(440 mg) as pale-yellow powder crystals.

¹H-NMR (CDCl₃) δ 1.37 (3H, t, J=7.2 Hz), 4.36 (2H, q, J=7.2 Hz), 5.33(2H, s), 5.91 (2H, s), 6.39 (1H, d, J=3.4 Hz), 6.57 (1H, d, J=2.6 Hz),7.12 (1H, d, J=3.4 Hz), 7.23 (1H, d, J=9.0 Hz), 7.43 (1H, dd, J=4.8, 7.8Hz), 7.50 (1H, dd, J=2.2, 9.2 Hz), 7.61 (1H, d, J=7.8 Hz), 7.75 (2H, s),7.90 (1H, dt, J=1.2, 7.8 Hz), 8.14 (1H, d, J=4.8 Hz), 8.30 (1H, s), 8.55(1H, br s).

Example 30

Production of5-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]-2-furancarboxylicacid

To a solution of ethyl5-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]-2-furoate(440 mg) in a mixed solvent of tetrahydrofuran (2.0 mL) and ethanol (2.0mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and themixture was stirred at room temperature for 5 hrs. 1N Hydrochloric acid(2.0 mL) and water (25 mL) were added to the reaction mixture, and themixture was stirred at room temperature for 30 min. The resultantprecipitate was collected by filtration, washed with water (10 mL×3) anddiisopropyl ether (10 mL×3), and dried under reduced pressure (80° C.)to give the title compound (310 mg) as white powder crystals.

¹H-NMR (DMSO-d₆) δ 5.27 (2H, s), 5.88 (2H, s), 6.35 (1H, d, J=3.4 Hz),6.53 (1H, d, J=2.6 Hz), 7.08 (1H, d, J=3.4 Hz), 7.20 (1H, d, J=9.0 Hz),7.37 (1H, dd, J=4.8, 7.8 Hz), 7.47 (1H, dd, J=2.2, 9.2 Hz), 7.58 (1H, d,J=7.8 Hz), 7.73 (2H, s), 7.88 (1H, t, J=1.2, 7.8 Hz), 8.27 (1H, s), 8.53(1H, br s), 8.59 (1H, d, J=4.8 Hz).

Example 31

Production of ethyl2-(3,5-dichlorophenoxy)-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoate

To a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (61 mg) in1-methyl-2-pyrrolidone (0.8 mL), was added ethyl5-amino-2-(3,5-dichlorophenoxy)benzoate (186 mg), and the mixture washeated to 140° C. and stirred for 2.5 hrs. The reaction mixture wasallowed to cool to room temperature, diluted with 5% aqueous sodiumhydrogen carbonate solution (20 mL), and extracted with a mixed solvent(25 mL×3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the obtainedresidue was subjected to silica gel column chromatography (basic silicagel, eluent:hexane/ethyl acetate=8/2→0/10). The object fraction wasconcentrated under reduced pressure. Ethyl acetate was added to theresidue, and the resultant precipitate was collected by filtration anddried under reduced pressure to give the title compound (149 mg) aspale-yellow powder crystals.

¹H-NMR (DMSO-d₆) δ 1.10 (3H, t, J=7.2 Hz), 4.18 (2H, q, J=7.2 Hz), 6.52(1H, d, J=2.8 Hz), 6.90 (2H, t, J=3.0 Hz), 7.28 (1H, dd, J=1.8, 2.8 Hz),7.33 (1H, dd, J=8.8 Hz), 7.71 (1H, d, J=2.8 Hz), 8.36 (2H, d, J=8.8 Hz),8.39 (1H, d, J=1.8 Hz), 9.60 (1H, s), 11.15 (1H, s).

Example 32

Production of2-(3,5-dichlorophenoxy)-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoicacid

To a solution of ethyl2-(3,5-dichlorophenoxy)-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoate(100 mg) in a mixed solvent of tetrahydrofuran (0.68 mL) and ethanol(0.68 mL) was added 1N aqueous sodium hydroxide solution (0.68 mL), andthe mixture was stirred at room temperature for 16 hrs. 1N Hydrochloricacid (0.68 mL) and water (5 mL) were added to the reaction mixture, andthe mixture was stirred at room temperature for 30 min. The resultantprecipitate was collected by filtration, washed with water (10 mL×3) anddiisopropyl ether (10 mL×3) and dried under reduced pressure (80° C.) togive the title compound (76 mg) as white powder crystals.

¹H-NMR (DMSO-d₆) δ 6.52 (1H, d, J=1.2 Hz), 6.90 (2H, t, J=1.2 Hz), 7.28(2H, dt, J=3.0, 5.1 Hz), 7.71 (1H, t, J=2.7 Hz), 8.29 (1H, dd, J=2.7,8.7 Hz), 8.37 (1H, d, J=2.7 Hz), 8.40 (1H, d, J=1.2 Hz), 9.59 (1H, s),11.18 (1H, br s).

Example 33

Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-ethyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production of 4-chloro-5-ethyl-5H-pyrrolo[3,2-d]pyrimidine

To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg) inN,N-dimethylformamide (1.3 mL) was added potassium carbonate (269 mg)under ice-cooling, and the mixture was stirred while warming to roomtemperature for 15 min.

Iodoethane (305 mg) was added to the reaction mixture, and the mixturewas stirred at room temperature for 3 hrs. The reaction mixture wasdiluted with water (20 mL) and extracted with ethyl acetate (30 mL×3).The organic layer was washed with saturated brine (20 mL×3) and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the obtained residue was subjected to silica gelcolumn chromatography (silica gel, eluent:hexane/ethylacetate=80/20→10/90). The object fraction was concentrated under reducedpressure and dried to give the title compound (187 mg) as a pale-yellowsolid.

¹H-NMR (CDCl₃) δ 1.52 (3H, t, J=7.2 Hz), 4.55 (2H, q, J=7.2 Hz), 6.73(1H, d, J=3.2 Hz), 7.51 (1H, d, J=3.2 Hz), 8.70 (1H, s).

(ii) Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-ethyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a solution of 4-chloro-5-ethyl-5H-pyrrolo[3,2-d]pyrimidine (85 mg) in1-methyl-2-pyrrolidone (0.94 mL) was added3-chloro-4-[(3-fluorobenzyl)oxy]aniline (177 mg). The title compound (98mg) was obtained as a pale-purple powder crystals by the reaction in thesame manner as in Example 29.

¹H-NMR (CDCl₃) δ 1.56 (3H, t, J=7.4 Hz), 4.33 (2H, q, J=7.4 Hz), 5.15(2H, s), 6.51 (1H, br s), 6.58 (1H, d, J=3.0 Hz), 6.72 (2H, s), 6.95(1H, d, J=8.7 Hz), 7.02 (1H, m), 7.21 (1H, d, J=8.5 Hz), 7.25 (1H, d,J=3.0 Hz), 7.33-7.40 (2H, m), 7.60 (1H, d, J=2.5 Hz), 8.49 (1H, br s).

Example 34

Production of5-ethyl-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a solution of 4-chloro-5-ethyl-5H-pyrrolo[3,2-d]pyrimidine (85 mg) in1-methyl-2-pyrrolidone (0.94 mL) was added3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (150 mg). The titlecompound (67 mg) was obtained as white powder crystals by the reactionin the same manner as in Example 29.

¹H-NMR (CDCl₃) δ 1.57 (3H, t, J=7.4 Hz), 2.25 (3H, s), 2.53 (3H, s),4.35 (2H, q, J=7.4 Hz), 6.58 (1H, d, J=3.0 Hz), 6.67 (1H, br s), 6.89(1H, d, J=8.7 Hz), 7.08 (1H, d, J=8.5 Hz), 7.13 (1H, dd, J=3.0, 8.7 Hz),7.25 (1H, d, J=3.0 Hz), 7.34 (1H, dd, J=2.6, 8.7 Hz), 7.42 (1H, d, J=2.5Hz), 8.23 (1H, d, 1H, J=2.5 Hz), 8.50 (1H, s).

Example 35

Production ofN-benzyl-N′-[3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)phenyl]urea

To a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (100 mg) in1-methyl-2-pyrrolidone (1.3 mL), was addedN-(3-aminophenyl)-N′-benzylurea (220 mg), and the mixture was heated to140° C. and stirred for 1.5 hrs. The reaction mixture was allowed tocool to room temperature, diluted with 5% aqueous sodium hydrogencarbonate solution (20 mL), and extracted with a mixed solvent (30 mL×3)of ethyl acetate/tetrahydrofuran (1/1). The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the obtained residuewas subjected to silica gel column chromatography (basic silica gel,eluent:ethyl acetate/methanol=100/0→85/15). The object fraction wasconcentrated under reduced pressure. Ethyl acetate was added to theresidue, and the resultant precipitate was collected by filtration anddried under reduced pressure to give the title compound (97 mg) aspale-yellow powder crystals.

¹H-NMR (DMSO-d₆) δ 4.32 (2H, d, J=5.8 Hz), 6.47 (1H, s), 6.63 (1H, t,J=5.8 Hz), 7.02 (1H, d, J=8.4 Hz), 7.16-7.32 (6H, m), 7.62 (2H, d, J=8.4Hz), 7.98 (1H, s), 8.33 (1H, s), 8.63 (1H, s), 9.15 (1H, s), 11.22 (1H,s).

Example 36

Production of4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-N-(2-hydroxyethyl)benzamide

To a solution of4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoicacid (126 mg) in N,N-dimethylformamide (1.2 mL) were addedN-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (72 mg)and 1-hydroxypyrrolidine-2,5-dione (43 mg), and the mixture was stirredat room temperature for 3 hrs. To this reaction mixture was addeddropwise a solution of 2-aminoethanol (23 mg) in a mixed solvent ofN,N-dimethylformamide (1.2 mL) and 10% aqueous sodium hydrogen carbonate(1.2 mL), and the mixture was stirred at room temperature for 48 hrs.The reaction mixture was diluted with water (25 mL) and extracted withethyl acetate (25 mL×3). The organic layer was washed with saturatedbrine (25 mL×3), and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the obtained residue wassubjected to silica gel column chromatography (basic silica gel,eluent:ethyl acetate/methanol=10/0→8/2). The object fraction wasconcentrated under reduced pressure. Chloroform/diisopropyl ether (1/4)was added to the residue, and the resultant precipitate was collected byfiltration and dried under reduced pressure to give the title compound(105 mg) as white powder crystals.

¹H-NMR (DMSO-d₆) δ 3.27 (2H, t, J=5.9 Hz), 3.41-3.48 (2H, m), 4.68 (1H,t, J=5.9 Hz), 5.21 (2H, s), 5.84 (2H, s), 6.56 (1H, d, J=3.0 Hz), 7.06(2H, d, J=8.1 Hz), 7.08 (2H, t, J=7.5 Hz), 7.27-7.35 (3H, m), 7.46 (1H,dt, J=5.8, 8.1 Hz), 7.64 (1H, d, J=2.5 Hz), 7.73 (2H, d, J=8.3 Hz), 7.82(1H, d, J=3.0 Hz), 8.27 (2H, s), 8.33 (1H, t, J=5.4 Hz).

Example 37

Production ofN-(3-amino-3-oxopropyl)-4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzamide

The title compound (83 mg) was obtained as white powder crystals by thereaction in the same manner as in Example 27 using4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoicacid (120 mg) and P-alaninamide hydrochloride (45 mg).

¹H-NMR (DMSO-d₆) δ 2.29 (1H, t, J=7.2 Hz), 3.37-3.42 (4H, m), 5.21 (2H,s), 5.83 (2H, s), 6.56 (1H, d, J=3.3 Hz), 6.80 (1H, br s), 7.06 (2H, d,J=8.3 Hz), 7.18 (2H, t, J=9.0 Hz), 7.29-7.34 (4H, m), 7.46 (1H, dt,J=5.8, 7.9 Hz), 7.63 (1H, d, J=2.4 Hz), 7.71 (2H, d, J=8.3 Hz), 7.81(1H, d, J=3.2 Hz), 8.26 (1H, d, J=3.3 Hz), 8.40 (1H, t, J=5.7 Hz).

Example 38

Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(2-ethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production of 4-chloro-5-(2-ethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine

To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg) inN,N-dimethylformamide (4.5 mL) was added cesium carbonate (1324 mg)under ice-cooling, and the mixture was stirred while warming to roomtemperature for 15 min. 1-Bromo-2-ethoxyethane (1016 mg) was added tothe reaction mixture, and the mixture was stirred at room temperaturefor 14 hrs. The reaction mixture was diluted with water (100 mL) andextracted with ethyl acetate (120 mL×3). The organic layer was washedwith saturated brine (100 mL×3) and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theobtained residue was subjected to silica gel column chromatography(silica gel, eluent:hexane/ethyl acetate=85/15→20/80). The objectfraction was concentrated under reduced pressure and dried to give thetitle compound (697 mg) as a pale-yellow oil.

¹H-NMR (CDCl₃) δ 1.13 (3H, t, J=6.9 Hz), 3.43 (2H, q, J=6.9 Hz), 3.78(2H, t, J=5.1 Hz), 4.67 (2H, t, J=5.1 Hz), 6.71 (1H, d, J=3.0 Hz), 7.59(1H, d, J=3.0 Hz), 8.70 (1H, s).

(ii) Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(2-ethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a solution of 4-chloro-5-(2-ethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine(90 mg) in 1-methyl-2-pyrrolidone (0.7 mL),3-chloro-4-[(3-fluorobenzyl)oxy]aniline (151 mg) was added, and themixture was heated to 140° C. and stirred for 7 hrs. The reactionmixture was allowed to cool to room temperature. The reaction mixturewas diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL)and extracted with ethyl acetate (25 mL×3). The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the obtained residuewas subjected to silica gel column chromatography (basic silica gel,eluent:ethyl acetate/methanol=10/0→8/2). The object fraction wasconcentrated under reduced pressure. The residue was recrystallized fromdiisopropyl ether, collected by filtration and dried under reducedpressure to give the title compound (90 mg) as pale-yellow needlecrystals.

¹H-NMR (CDCl₃) δ 1.22 (3H, t, J=7.0 Hz), 3.63 (2H, q, J=7.0 Hz), 3.90(2H, t, J=4.4 Hz), 4.50 (2H, t, J=4.4 Hz), 5.13 (2H, s), 6.61 (1H, d,J=3.2 Hz), 6.94 (1H, d, J=8.9 Hz), 7.01 (1H, t, J=8.1 Hz), 7.17-7.25(3H, m), 7.35 (1H, dt, J=5.6, 7.9 Hz), 7.47 (1H, dd, J=1.3, 8.9 Hz),7.64 (1H, d, J=2.6 Hz), 8.48 (1H, s), 8.79 (1H, s).

Example 39

Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production of 4-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine

To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (320 mg) inN,N-dimethylformamide (2.0 mL), was added potassium carbonate (452 mg)under ice-cooling, and the mixture was stirred while warming to roomtemperature for 15 min. Iodomethane (444 mg) was added to the reactionmixture, and the mixture was stirred at room temperature for 3 hrs. Thereaction mixture was diluted with water (25 mL) and extracted with ethylacetate (30 mL×3). The organic layer was washed with saturated brine (20mL×3) and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the obtained residue wassubjected to silica gel column chromatography (silica gel,eluent:hexane/ethyl acetate=80/20→10/90). The object fraction wasconcentrated under reduced pressure and dried to give the title compound(325 mg) as a pale-yellow solid.

¹H-NMR (CDCl₃) δ 4.16 (3H, s), 6.70 (1H, d, J=3.9 Hz), 7.42 (1H, d,J=3.9 Hz), 8.69 (1H, s).

(ii) Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a solution of 4-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (100 mg)in 1-methyl-2-pyrrolidone (1.0 mL) was added3-chloro-4-[(3-fluorobenzyl)oxy]aniline (225 mg), and the mixture washeated to 140° C. and stirred for 1.5 hrs. The reaction mixture wasallowed to cool to room temperature, diluted with 5% aqueous sodiumhydrogen carbonate solution (25 mL), and extracted with ethyl acetate(30 mL×3). The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the obtained residue was subjected to silica gelcolumn chromatography (eluent:hexane/ethyl acetate=95/5->0/100). Theobject fraction was concentrated under reduced pressure. The residue wasrecrystallized from a mixed solvent of diisopropyl ether and chloroform,collected by filtration and dried under reduced pressure to give thetitle compound (121 mg) as a pale-purple powder crystals.

¹H-NMR (DMSO-d₆) δ 4.14 (3H, s), 5.24 (2H, s), 6.42 (1H, d, J=3.0 Hz),7.16-7.23 (2H, m), 7.29-7.34 (2H, m), 7.44-7.56 (3H, m), 7.78 (1H, d,J=2.4 Hz), 8.24 (1H, s), 8.36 (1H, s).

Example 40

Production of 5-methyl-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a solution of 4-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (100 mg)in 1-methyl-2-pyrrolidone (1.0 mL) was added3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (192 mg).

The title compound (106 mg) was obtained as white powder crystals by thereaction in the same manner as in Example 39 (ii).

¹H-NMR (DMSO-d₆) δ 2.17 (3H, s), 2.44 (3H, s), 4.15 (3H, s), 6.43 (1H,dd, J=0.9, 3.0 Hz), 6.94 (1H, d, J=8.4 Hz), 7.18 (1H, dd, J=3.0, 8.4Hz), 7.24 (1H, d, J=8.7 Hz), 7.51 (1H, d, J=8.7 Hz), 7.56 (1H, d, J=3.0Hz), 8.17 (1H, d, J=3.0 Hz), 8.25 (1H, d, J=0.9 Hz), 8.40 (1H, s), 8.63(1H, s).

Example 41

Production of2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethanol(i) Production of5-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidine

To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (307 mg) inN,N-dimethylformamide (2.0 mL) was added cesium carbonate (977 mg) underice-cooling, and the mixture was stirred while warming to roomtemperature for 15 min. To the reaction mixture was addedtert-butyl(2-iodoethoxy)dimethylsilane (839 mg), and the mixture wasstirred at room temperature for 16 hrs. The reaction mixture was dilutedwith water (20 mL) and extracted with ethyl acetate (30 mL×3). Theorganic layer was washed with saturated brine (30 mL×3) and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the obtained residue was subjected to silica gel columnchromatography (silica gel, eluent:hexane/ethyl acetate=85/15→10/90).The object fraction was concentrated under reduced pressure and dried togive the title compound (591 mg) as a white solid.

¹H-NMR (DMSO-d₆) δ 0.95 (9H, s), 4.10 (2H, t, J=5.2 Hz), 4.76 (2H, t,J=5.2 Hz), 6.87 (1H, d, J=3.0 Hz), 7.57 (1H, d, J=3.0 Hz), 8.85 (1H, s).

(ii) Production of 2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethanol

To a solution of5-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidine(560 mg) in tetrahydrofuran (1.7 mL), was added tetrabutylammoniumfluoride (1M tetrahydrofuran solution) (2.69 mL) under ice-cooling, andthe mixture was stirred for 4 hrs. The reaction mixture was diluted withwater (20 mL) and extracted with ethyl acetate (30 mL×3). The organiclayer was washed with saturated brine (30 mL×3) and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the obtained residue was subjected to silica gel columnchromatography (silica gel, eluent:ethyl acetate/methanol=10/0→9/1). Theobject fraction was concentrated under reduced pressure and dried togive the title compound (391 mg) as a white solid.

¹H-NMR (CDCl₃) δ 2.13 (2H, td, J=6.3, 12.6 Hz), 4.66 (2H, t, J=6.3 Hz),6.72 (1H, d, J=3.0 Hz), 7.57 (1H, d, J=3.0 Hz), 8.70 (1H, s).

(iii) Production of2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethanol

To a solution of 2-(4-chloro-5H-pyrrolo[3,2-O]pyrimidin-5-yl)ethanol(130 mg) in 1-methyl-2-pyrrolidone (1.3 mL) was added3-chloro-4-[(3-fluorobenzyl)oxy]aniline (193 mg), and the reactionmixture was stirred at 120° C. for 2 hrs. The reaction mixture wasallowed to cool to room temperature and ethyl acetate (20 mL) was added.The resultant precipitate was recrystallized from a mixed solvent ofhexane/methanol (3/7), collected by filtration and dried under reducedpressure to give the title compound (206 mg) as pale purple crystals.

¹H-NMR (DMSO-d₆) δ 3.86 (2H, t, J=4.3 Hz), 4.54 (2H, m), 5.24 (2H, s),6.23 (1H, br s), 6.53 (1H, d, J=3.2 Hz), 7.18 (1H, dt, J=2.6, 8.1 Hz),7.25 (1H, d, J=9.0 Hz), 7.29-7.34 (2H, m), 7.43-7.51 (2H, m), 7.70 (1H,d, J=3.2 Hz), 7.78 (1H, d, J=2.6 Hz), 8.37 (1H, br s), 9.82 (1H, br s).

Example 42

Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-propyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production of 4-chloro-5-propyl-5H-pyrrolo[3,2-d]pyrimidine

To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (150 mg) inN,N-dimethylformamide (1.6 mL) was added cesium carbonate (798 mg) underice-cooling, and the mixture was stirred while warming to roomtemperature for 15 min. To the reaction mixture was added 1-bromopropane(301 mg), and the mixture was stirred at room temperature for 15 hrs.The reaction mixture was diluted with water (20 mL) and extracted withethyl acetate (30 mL×3). The organic layer was washed with saturatedbrine (30 mL×3) and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the obtained residue wassubjected to silica gel column chromatography (silica gel,eluent:hexane/ethyl acetate=90/10→20/80). The object fraction wasconcentrated under reduced pressure and dried to give the title compound(161 mg) as a white solid.

¹H-NMR (CDCl₃) δ 0.96 (3H, t, J=7.5 Hz), 1.86-1.98 (2H, m), 4.44 (2H, t,J=7.5 Hz), 6.73 (1H, t, J=3.3 Hz), 7.48 (1H, d, J=3.3 Hz), 8.70 (1H, s).

(ii) Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-propyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a solution of 4-chloro-5-propyl-5H-pyrrolo[3,2-d]pyrimidine (80 mg)in 1-methyl-2-pyrrolidone (0.8 mL) was added3-chloro-4-[(3-fluorobenzyl)oxy]aniline (193 mg), and the reactionmixture was stirred at 120° C. for 2 hrs. The reaction mixture wasallowed to cool to room temperature, diluted with 5% aqueous sodiumhydrogen carbonate solution (25 mL), and extracted with ethyl acetate(30 mL×3). The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the obtained residue was subjected to silica gelcolumn chromatography (eluent:ethyl acetate/methanol=100/0→95/5). Theobject fraction was concentrated under reduced pressure. To the residuewas added a mixed solvent of diisopropyl ether and chloroform. Theresultant precipitate was collected by filtration and dried underreduced pressure to give the title compound (96 mg) as a pale-purplepowder.

¹H-NMR (DMSO-d₆) δ 0.85 (3H, t, J=6.0 Hz), 1.81 (2H, q, J=6.9 Hz), 4.42(2H, t, J=6.9 Hz), 5.18 (2H, s), 6.47 (1H, dd, J=1.8, 3.0 Hz), 7.02 (1H,d, J=8.7 Hz), 7.06 (1H, d, J=2.4 Hz), 7.21-7.49 (4H, m), 7.71 (1H, d,J=2.4 Hz), 7.77 (1H, br s), 8.07 (1H, br s), 8.34 (1H, d, J=2.1 Hz).

Example 43

Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-isobutyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production of 4-chloro-5-isobutyl-5H-pyrrolo[3,2-d]pyrimidine

To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (150 mg) inN,N-dimethylformamide (1.6 mL) was added cesium carbonate (478 mg) underice-cooling, and the mixture was stirred while warming to roomtemperature for 15 min. To the reaction mixture was added1-bromo-2-methylpropane (336 mg), and the mixture was stirred at roomtemperature for 19 hrs. The reaction mixture was diluted with water (20mL) and extracted with ethyl acetate (30 mL×3). The organic layer waswashed with saturated brine (30 mL×3) and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theobtained residue was subjected to silica gel column chromatography(silica gel, eluent:hexane/ethyl acetate=90/10→20/80). The objectfraction was concentrated under reduced pressure and dried to give thetitle compound (210 mg) as a white solid.

¹H-NMR (CDCl₃) δ 0.94 (6H, d, J=6.6 Hz), 2.14-2.27 (1H, m), 4.26 (2H, d,J=7.5 Hz), 6.72 (1H, d, J=2.4 Hz), 7.46 (1H, d, J=2.4 Hz), 8.70 (1H, s).

(ii) Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-isobutyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

The title compound (89 mg) was obtained as a pale-purple powder by thereaction in the same manner as in Example 42 (ii) using a solution of4-chloro-5-isobutyl-5H-pyrrolo[3,2-d]pyrimidine (90 mg) in1-methyl-2-pyrrolidone (0.8 mL).

¹H-NMR (DMSO-d₆) δ 0.83 (6H, d, J=6.3 Hz), 2.08 (1H, m), 4.24 (2H, d,J=7.5 Hz), 5.17 (2H, s), 6.47 (1H, d, J=2.7 Hz), 7.02 (2H, d, J=8.7 Hz),7.22-7.29 (2H, m), 7.32 (1H, d, J=3.0 Hz), 7.40 (1H, dt, J=6.0, 8.1 Hz),7.46 (1H, dd, J=2.7, 9.0 Hz), 7.73 (1H, d, J=2.7 Hz), 7.79 (1H, s), 8.09(1H, br s).

Example 44

Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(tetrahydrofuran-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production of4-chloro-5-(tetrahydrofuran-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidine

To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (150 mg) inN,N-dimethylformamide (1.0 mL) was added cesium carbonate (478 mg) underice-cooling, and the mixture was stirred while warming to roomtemperature for 15 min. To the reaction mixture was added2-(bromomethyl)tetrahydrofuran (242 mg), and the mixture was stirred atroom temperature for 26 hrs. The reaction mixture was diluted with water(20 mL) and extracted with ethyl acetate (30 mL×3). The organic layerwas washed with saturated brine (30 mL×3) and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the obtained residue was subjected to silica gel columnchromatography (silica gel, eluent:hexane/ethyl acetate=90/10→20/80).The object fraction was concentrated under reduced pressure and dried togive the title compound (200 mg) as a colorless oil.

¹H-NMR (CDCl₃) δ 1.47-1.64 (1H, m), 1.85-2.17 (3H, m), 3.75-3.90 (2H,m), 4.18-4.31 (1H, m), 4.42-4.53 (1H, m), 4.71 (1H, dd, J=3.4, 14.6 Hz),6.74 (1H, d, J=3.0 Hz), 7.63 (1H, d, J=3.0 Hz), 8.70 (1H, s).

(ii) Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(tetrahydrofuran-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

The title compound (139 mg) was obtained as white powder by the reactionin the same manner as in Example 42 (ii) using a solution of4-chloro-5-(tetrahydrofuran-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidine (200mg) in 1-methyl-2-pyrrolidone (1.6 mL).

¹H-NMR (DMSO-d₆) δ 1.56-1.65 (2H, m), 1.78-1.80 (1H, m), 1.97-2.07 (1H,m), 3.70 (2H, m), 4.17-4.19 (1H, m), 4.43 (1H, dd, J=6.0, 15.0 Hz), 4.67(1H, d, J=13.8 Hz), 5.21 (2H, s), 7.14 (1H, dd, J=8.1 Hz), 7.20 (1H, d,J=8.1 Hz), 7.27-7.48 (4H, m), 7.61 (1H, d, J=2.1 Hz), 7.78 (1H, d, J=1.5Hz), 8.25 (1H, d, J=1.2 Hz), 8.60 (1H, d, J=1.2 Hz), 9.03 (1H, s).

Example 45

Production of methyl3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoate(i) Production of methyl3-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoate

To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (300 mg) inN,N-dimethylformamide (2.0 mL) was added cesium carbonate (955 mg) underice-cooling, and the mixture was stirred while warming to roomtemperature for 15 min. To the reaction mixture was added methyl3-(bromomethyl)benzoate (671 mg), and the mixture was stirred at roomtemperature for 4 hrs. The reaction mixture was diluted with water (40mL), and extracted with a mixed solvent (40 mL×3) of ethylacetate/tetrahydrofuran (1/1). The organic layer was washed withsaturated brine (120 mL×3) and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the obtainedresidue was subjected to silica gel column chromatography (silica gel,eluent:hexane/ethyl acetate=80/20→10/90). The object fraction wasconcentrated under reduced pressure. Chloroform/diisopropyl ether (4/1)was added to the residue, and the resultant precipitate was collected byfiltration, washed and dried under reduced pressure to give the titlecompound (319 mg) as a pale-brown powder.

¹H-NMR (CDCl₃) δ 3.90 (3H, s), 5.77 (2H, s), 6.82 (1H, d, J=3.4 Hz),7.19 (1H, dd, J=1.2, 7.8 Hz), 7.41 (1H, t, J=7.8 Hz), 7.54 (1H, d, J=3.4Hz), 7.82 (1H, s), 7.98 (1H, dt, J=1.2, 7.8 Hz), 8.73 (1H, s).

(ii) Production of methyl3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoate

To a solution of methyl3-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoate (670 mg) in1-methyl-2-pyrrolidone (3.0 mL) was added3-chloro-4-[(3-fluorobenzyl)oxy]aniline (549 mg), and the reactionmixture was stirred at 120° C. for 1.5 hrs. The reaction mixture wasallowed to cool to room temperature, diluted with 5% aqueous sodiumhydrogen carbonate solution (50 mL), and extracted with ethyl acetate(50 mL×3). The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the obtained residue was subjected to silica gelcolumn chromatography (basic silica gel, eluent:hexane/ethylacetate=9/1→0/10). The object fraction was concentrated under reducedpressure and dried to give the title compound (1010 mg) as a yellow oil.

¹H-NMR (CDCl₃) δ 3.93 (3H, s), 5.08 (2H, s), 5.60 (2H, s), 6.39 (1H, s),6.67 (1H, d, J=3.4 Hz), 6.82 (1H, d, J=9.2 Hz), 7.01 (2H, dd, J=2.6, 8.8Hz), 7.16-7.40 (3H, m), 7.56 (1H, t, J=7.8 Hz), 7.94 (1H, s), 8.09 (1H,d, J=7.8 Hz), 8.47 (1H, s).

Example 46

Production of3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoicacid

To a solution of methyl3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoate(800 mg) in a mixed solvent of tetrahydrofuran (4.0 mL) and methanol(4.0 mL) was added 1N aqueous sodium hydroxide solution (4.0 mL), andthe mixture was stirred at room temperature for 12 hrs. 1N Hydrochloricacid (4.0 mL) and water (15 mL) were added to the reaction mixture, andthe mixture was stirred at room temperature for 30 min. The resultantprecipitate was collected by filtration, washed with water (10 mL×3) anddiisopropyl ether (10 mL×3) and dried under reduced pressure (80° C.) togive the title compound (610 mg) as a white powder.

¹H-NMR (DMSO-d₆) δ 5.21 (2H, s), 5.86 (2H, s), 6.57 (1H, dd, J=1.5, 3.3Hz), 7.14-7.51 (8H, m), 7.58 (1H, dd, J=1.5, 2.4 Hz), 7.69 (1H, s), 7.78(1H, d, J=6.3 Hz), 7.84 (1H, d, J=1.8 Hz), 8.27 (1H, d, J=1.5 Hz), 8.30(1H, s).

Example 47

Production of5-(2-ethoxyethyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-0]pyrimidin-4-amine

To a solution of 4-chloro-5-(2-ethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine(160 mg) in 1-methyl-2-pyrrolidone (1.4 mL) was added3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (228 mg), and the reactionmixture was stirred at 120° C. for 2 hrs. The reaction mixture wasallowed to cool to room temperature, diluted with 5% aqueous sodiumhydrogen carbonate solution (25 mL), and extracted with ethyl acetate(40 mL×3). The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the obtained residue was subjected to silica gelcolumn chromatography (eluent:hexane/ethyl acetate=90/10→0/100). Theobject fraction was concentrated under reduced pressure and dried togive the title compound (191 mg) as a colorless transparent oil.

¹H-NMR (CDCl₃) δ 1.25 (3H, dt, J=2.1, 7.2 Hz), 2.14 (3H, s), 2.52 (3H,s), 3.65 (2H, q, J=7.2 Hz), 3.92 (2H, t, J=4.5 Hz), 4.54 (2H, t, J=4.5Hz), 6.62 (1H, d, J=3.0 Hz), 6.91 (1H, d, J=8.4 Hz), 7.11 (1H, dd,J=2.7, 8.4 Hz), 7.20 (1H, d, J=3.0 Hz), 7.40 (1H, dd, J=2.7, 8.4 Hz),7.51 (1H, d, J=3.0 Hz), 8.26 (1H, dd, J=0.6, 2.7 Hz), 8.50 (1H, s), 8.84(1H, br s).

Example 48

Production ofN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-(2-ethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a solution of 4-chloro-5-(2-ethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine(160 mg) in 1-methyl-2-pyrrolidone (1.4 mL) was added3-chloro-4-(pyridin-2-ylmethoxy)aniline (250 mg). The title compound(160 mg) was obtained as pale-yellow needle crystals by the reaction inthe same manner as in Example 42 (ii).

¹H-NMR (CDCl₃) δ 1.23 (3H, t, J=7.2 Hz), 3.64 (2H, q, J=7.2 Hz), 3.91(2H, t, J=7.2 Hz), 4.51 (2H, t, J=7.2 Hz), 5.27 (2H, s), 6.12 (1H, s),6.61 (1H, d, J=3.3 Hz), 6.97 (1H, d, J=8.7 Hz), 7.18 (1H, d, J=3.3 Hz),7.42 (1H, dd, J=2.7, 8.7 Hz), 7.66 (1H, s), 7.69 (1H, d, J=2.1 Hz), 7.76(1H, dt, J=1.5, 8.7 Hz), 8.49 (1H, s), 8.60 (1H, d, J=4.5 Hz), 8.81 (1H,s).

Example 49

Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(2-fluoroethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production of 4-chloro-5-(2-fluoroethyl)-5H-pyrrolo[3,2-d]pyrimidine

To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (100 mg) inN,N-dimethylformamide (0.6 mL) was added cesium carbonate (281 mg) underice-cooling, and the mixture was stirred while warming to roomtemperature for 15 min. To the reaction mixture was added1-bromo-2-fluoroethane (124 mg), and the mixture was stirred at roomtemperature for 5 hrs. The reaction mixture was diluted with water (20mL) and extracted with ethyl acetate (20 mL×3). The organic layer waswashed with saturated brine (20 mL×3) and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theobtained residue was subjected to silica gel column chromatography(silica gel, eluent:hexane/ethyl acetate=90/10→0/10). The objectfraction was concentrated under reduced pressure and dried to give thetitle compound (110 mg) as a colorless transparent oil.

¹H-NMR (CDCl₃) δ 4.64-4.69 (1H, m), 4.75-4.79 (1H, m), 4.91 (2H, d,J=5.1 Hz), 6.77 (1H, dd, J=1.4, 3.4 Hz), 7.57 (1H, d, J=3.4 Hz), 8.73(1H, s).

(ii) Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(2-fluoroethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

The title compound (124 mg) was obtained as white powder crystals by thereaction in the same manner as in Example 39 (ii) using a solution of4-chloro-5-(2-fluoroethyl)-5H-pyrrolo[3,2-d]pyrimidine (110 mg) in1-methyl-2-pyrrolidone (1.0 mL).

¹H-NMR (CDCl₃) δ 4.65(2H, dt, J=4.0, 29.0 Hz), 4.90 (2H, dt, J=4.0, 47.2Hz), 5.14 (2H, s), 6.65 (1H, d, J=3.0 Hz), 6.93 (1H, d, J=8.8 Hz), 7.04(1H, d, J=8.8 Hz), 7.21-7.41 (6H, m), 7.55 (1H, s), 8.48 (1H, s).

Example 50

Production of3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-N-(2-hydroxyethyl)benzamide

The title compound (93 mg) was obtained as white powder crystals by thereaction in the same manner as in Example 36 using3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoicacid (126 mg).

¹H-NMR (DMSO-d₆) δ 3.26-3.48 (4H, m), 4.71 (1H, t, J=5.6 Hz), 5.21 (2H,s), 5.83 (2H, s), 6.55 (1H, d, J=2.6 Hz), 7.06-7.52 (7H, m), 7.61-7.72(4H, m), 7.80 (1H, d, J=3.2 Hz), 8.26 (2H, s), 8.39 (1H, m).

Example 51

Production of ethyl[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]acetate(i) Production of ethyl(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)acetate

To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg) inN,N-dimethylformamide (1.3 mL) was added cesium carbonate (615 mg) underice-cooling, and the mixture was stirred while warming to roomtemperature for 15 min. To the reaction mixture was added ethylbromoacetate (326 mg), and the mixture was stirred at room temperaturefor 2.5 hrs. The reaction mixture was diluted with water (20 mL) andextracted with ethyl acetate (20 mL×3). The organic layer was washedwith saturated brine (20 mL×3) and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theobtained residue was subjected to silica gel column chromatography(silica gel, eluent:hexane/ethyl acetate=90/10→0/10). The objectfraction was concentrated under reduced pressure and dried to give thetitle compound (210 mg) as white powder crystals.

¹H-NMR (DMSO-d₆) δ 1.29 (3H, t, J=7.2 Hz), 4.27 (2H, q, J=7.2 Hz), 5.21(2H, s), 6.80 (1H, d, J=3.3 Hz), 7.45 (1H, d, J=3.3 Hz), 8.74 (1H, s).

(ii) Production of ethyl[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]acetate

To a solution of ethyl (4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)acetate(140 mg) in isopropyl alcohol (0.6 mL) was added3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (188 mg), and the mixturewas stirred in an oil bath at a temperature of 110° C. for 2 hrs. Thereaction mixture was allowed to cool to room temperature, diluted with5% aqueous sodium hydrogen carbonate solution (20 mL) and extracted withethyl acetate (25 mL×3). The organic layer was washed with saturatedbrine and dried over anhydrous magnesium sulfate.

The solvent was evaporated under reduced pressure, and the obtainedresidue was subjected to silica gel column chromatography (basic silicagel, eluent:ethyl acetate/methanol=10/0→9/1). The object fraction wasconcentrated under reduced pressure. Diisopropyl ether was added to theresidue, and the resultant precipitate was collected by filtration anddried under reduced pressure to give the title compound (210 mg) aswhite powder crystals.

¹H-NMR (CDCl₃) δ 1.35 (3H, t, J=7.0 Hz), 2.25 (3H, s), 2.53 (3H, s),4.35 (2H, q, J=7.0 Hz), 4.96 (2H, s), 6.64 (1H, d, J=3.4 Hz), 6.90 (1H,d, J=8.8 Hz), 7.08 (1H, d, J=1.8 Hz), 7.09 (1H, d, J=2.6 Hz), 7.22 (1H,d, J=3.4 Hz), 7.37 (1H, d, J=8.8 Hz), 7.44 (1H, d, J=2.6 Hz), 8.17 (1H,br s), 8.26 (1H, d, J=1.8 Hz), 8.53 (1H, s).

Example 52

Production of[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]aceticacid

The title compound (101 mg) was obtained as white powder by the reactionin the same manner as in Example 46 using ethyl[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]acetate(200 mg).

¹H-NMR (DMSO-d₆) δ 2.43 (3H, s), 2.51 (3H, s), 5.30 (2H, s), 6.49 (1H,s), 6.92 (1H, d, J=8.8 Hz), 7.20-7.25 (2H, m), 7.37-7.44 (2H, m), 7.62(1H, s), 8.17 (1H, s), 8.31 (1H, s).

Example 53

Production of3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propan-1-ol(i) Production of5-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidine

To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (400 mg) inN,N-dimethylformamide (2.6 mL) was added cesium carbonate (957 mg) underice-cooling, and the mixture was stirred while warming to roomtemperature for 15 min. To the reaction mixture was added(3-bromopropoxy)(tert-butyl)dimethylsilane (979 mg), and the mixture wasstirred at room temperature for 16 hrs. The reaction mixture was dilutedwith water (20 mL) and extracted with ethyl acetate (30 mL×3). Theorganic layer was washed with saturated brine (30 mL×3) and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the obtained residue was subjected to silica gel columnchromatography (silica gel, eluent:hexane/ethyl acetate=85/15→10/90).The object fraction was concentrated under reduced pressure and dried togive the title compound (630 mg) as a white solid.

¹H-NMR (CDCl₃) δ 0.95 (9H, s), 2.83 (2H, t, J=5.2 Hz), 4.10 (2H, t,J=5.2 Hz), 4.76 (2H, t, J=5.2 Hz), 6.87 (1H, d, J=2.8 Hz), 7.71 (1H, d,J=2.8 Hz), 8.85 (1H, s).

(ii) Production of3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propan-1-ol

The title compound (320 mg) was obtained as white powder crystals by thereaction in the same manner as in Example 41 (ii) using5-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidine(600 mg).

¹H-NMR (CDCl₃) δ 2.13 (2H, dt, J=6.3, 12.6 Hz), 3.65 (2H, dd, J=6.3,10.2 Hz), 4.66 (2H, t, J=6.3 Hz), 6.72 (1H, d, J=3.0 Hz), 7.57 (1H, d,J=3.0 Hz), 8.70 (1H, s).

(iii) Production of3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propan-1-ol

The title compound (180 mg) was obtained as pale purple crystals by thereaction in the same manner as in Example 41 (iii) using3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propan-1-ol (100 mg).

¹H-NMR (DMSO-d₆) δ 1.98 (2H, t, J=6.0 Hz), 3.39 (2H, t, J=6.0 Hz), 4.66(2H, t, J=6.0 Hz), 5.30 (2H, s), 6.66 (1H, d, J=3.2 Hz), 7.19 (1H, dt,J=1.9, 8.3 Hz), 7.29-7.34 (3H, m), 7.44-7.52 (2H, m), 7.72 (1H, d, J=2.6Hz), 8.00 (1H, d, J=3.2 Hz), 8.66 (1H, s), 9.97 (1H, s).

Example 54

Production ofN-(2-hydroxyethyl)-2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]acetamide

The title compound (38 mg) was obtained as white powder by the reactionin the same manner as in Example 36 using[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenylamino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)aceticacid (70 mg).

¹H-NMR (DMSO-d₆) δ 2.17 (3H, s), 2.43 (3H, s), 3.24 (2H, dd, J=5.6, 11.3Hz), 3.47 (2H, dd, J=5.6, 11.3 Hz), 4.86 (1H, t, J=5.3 Hz), 5.04 (2H,s), 6.49 (1H, d, J=3.0 Hz), 6.97 (1H, d, J=8.5 Hz), 7.15 (1H, dd, J=2.8,8.5 Hz), 7.22 (1H, d, J=8.5 Hz), 7.54-7.57 (3H, m), 8.16 (1H, d, J=2.5Hz), 8.30 (1H, s), 8.91 (1H, t, J=5.6 Hz), 10.10 (1H, s).

Example 55

Production ofN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-(4,4,4-trifluorobutyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production of4-chloro-5-(4,4,4-trifluorobutyl)-5H-pyrrolo[3,2-d]pyrimidine

To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (250 mg) inN,N-dimethylformamide (1.6 mL) was added cesium carbonate (675 mg) underice-cooling, and the mixture was stirred while warming to roomtemperature for 15 min. To the reaction mixture was added4-bromo-1,1,1-trifluorobutane (466 mg), and the mixture was stirred atroom temperature for 15 hrs. The reaction mixture was diluted with water(20 mL) and extracted with ethyl acetate (20 mL×3). The organic layerwas washed with saturated brine (20 mL×3) and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the obtained residue was subjected to silica gel columnchromatography (silica gel, eluent:hexane/ethyl acetate=9/1→0/10). Theobject fraction was concentrated under reduced pressure and dried togive the title compound (440 mg) as a colorless transparent oil.

¹H-NMR (CDCl₃) δ 2.17 (4H, m), 4.57 (2H, t, J=6.6 Hz), 6.76 (1H, d,J=3.3 Hz), 7.47 (1H, d, J=3.3 Hz), 8.72 (1H, s).

(ii) Production ofN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-(4,4,4-trifluorobutyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

The title compound (171 mg) was obtained as colorless oil by thereaction in the same manner as in Example 38 using4-chloro-5-(4,4,4-trifluorobutyl)-5H-pyrrolo[3,2-d]pyrimidine (150 mg).

¹H-NMR (CDCl₃) δ 2.00-2.17 (4H, m), 2.25 (3H, s), 2.53 (3H, s), 4.29(2H, t, J=6.9 Hz), 6.54 (1H, br s), 6.63 (1H, d, J=3.2 Hz), 6.88 (1H, d,J=8.5 Hz), 7.09 (1H, d, J=8.5 Hz), 7.13 (1H, dd, J=2.6, 8.5 Hz), 7.20(1H, d, J=2.6 Hz), 7.23 (1H, d, J=3.2 Hz), 7.26 (1H, s), 7.32 (1H, d,J=2.6 Hz), 8.23 (1H, d, J=2.6 Hz), 8.54 (1H, s).

Example 56

Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-[2-(2-ethoxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production of4-chloro-5-[2-(2-ethoxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidine

To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (300 mg) inN,N-dimethylformamide (2.0 mL) was added cesium carbonate (728 mg) underice-cooling, and the mixture was stirred while warming to roomtemperature for 15 min. To the reaction mixture was added1-bromo-2-(2-ethoxyethoxy)ethane (496 mg), and the mixture was stirredat room temperature for 20 hrs. The reaction mixture was diluted withwater (20 mL) and extracted with ethyl acetate (20 mL×3). The organiclayer was washed with saturated brine (20 mL×3) and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the obtained residue was subjected to silica gel columnchromatography (silica gel, eluent:hexane/ethyl acetate=9/1→0/10). Theobject fraction was concentrated under reduced pressure and dried togive the title compound (440 mg) as a colorless transparent oil.

¹H-NMR (CDCl₃) δ 1.17 (3H, t, J=7.1 Hz), 3.40-3.58 (6H, m), 3.87 (2H, t,J=5.1 Hz), 4.69 (2H, t, J=5.1 Hz), 6.70 (1H, d, J=3.3 Hz), 7.63 (1H, d,J=3.3 Hz), 8.69 (1H, s).

(ii) Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-[2-(2-ethoxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a solution of4-chloro-5-[2-(2-ethoxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidine (150mg) in 1-methyl-2-pyrrolidone (1.1 mL) was added3-chloro-4-[(3-fluorobenzyl)oxy]aniline (189 mg), and the reactionmixture was stirred at 120° C. for 1 hr. The reaction mixture wasallowed to cool to room temperature, diluted with 5% aqueous sodiumhydrogen carbonate solution (25 mL), and extracted with ethyl acetate(30 mL×3). The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the obtained residue was subjected to silica gelcolumn chromatography (basic silica gel, eluent:ethylacetate/methanol=100/0→95/5). The object fraction was concentrated underreduced pressure and dried to give the title compound (146 mg) as acolorless oil.

¹H-NMR (CDCl₃) δ 1.09 (3H, t, J=6.9 Hz), 3.36 (2H, q, J=6.9 Hz), 3.51(2H, t, J=4.2 Hz), 3.71 (2H, t, J=4.5 Hz), 3.98 (2H, t, J=4.5 Hz), 4.51(2H, t, J=4.2 Hz), 5.24 (2H, s), 6.60 (1H, d, J=3.0 Hz), 6.91 (2H, d,J=8.8 Hz), 7.00 (2H, t, J=7.2 Hz), 7.17-7.37 (2H, m), 7.50 (1H, dd,J=2.7, 8.8 Hz), 7.68 (1H, d, J=3.0 Hz), 8.47 (1H, s), 8.68 (1H, s).

Example 57

Production of5-[2-(2-ethoxyethoxy)ethyl]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

The title compound (98 mg) was obtained as colorless oil by the reactionin the same manner as in Example 47 using4-chloro-5-[2-(2-ethoxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidine (150mg).

¹H-NMR (DMSO-d₆) δ 0.93 (3H, t, J=7.0 Hz), 2.24 (3H, s), 2.74 (3H, s),3.23 (2H, q, J=7.0 Hz), 3.37-3.40 (2H, m), 3.56-3.59 (2H, m), 3.86 (2H,t, J=4.5 Hz), 4.89 (2H, t, J=4.5 Hz), 6.72 (1H, d, J=3.0 Hz), 7.22 (1H,d, J=8.7 Hz), 7.58-7.66 (2H, m), 7.91 (1H, d, J=8.7 Hz), 8.05 (1H, t,J=3.0 Hz), 8.09 (1H, d, J=3.0 Hz), 8.36 (1H, d, J=2.8 Hz), 8.73 (1H, s),10.07 (1H, br s).

Example 58

Production of2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethanol

The title compound (241 mg) was obtained as white powder crystals by thereaction in the same manner as in Example 47 using2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethanol (250 mg).

¹H-NMR (DMSO-d₆) δ 2.17 (3H, s), 2.43 (3H, s), 3.87 (2H, t, J=4.5 Hz),4.52 (2H, t, J=4.5 Hz), 6.27 (1H, br s), 6.48 (1H, dd, J=1.6, 3.0 Hz),6.97 (1H, d, J=9.6 Hz), 7.16 (1H, ddd, J=1.6, 3.0, 8.7 Hz), 7.23 (1H, d,J=8.4 Hz), 7.53 (2H, br s), 7.63 (1H, dd, J=1.6, 3.0 Hz), 8.17 (1H, d,J=3.0 Hz), 8.28 (1H, d, J=1.6 Hz), 9.66 (1H, br s).

Example 59

Production of4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5,6-dihydro-4H-pyrrolo[3,2,1-de]pteridine

To a suspension of2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethanol(50 mg) and tributylphosphine (54 mg) in toluene (2.5 mL) was added1,1′-[(E)-diazene-1,2-diyldicarbonyl]dipiperidine (67 mg), and themixture was stirred at room temperature for 3 hrs. The reaction mixturewas diluted with water (15 mL) and extracted with ethyl acetate (20mL×3). The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the obtained residue was subjected to silica gel columnchromatography (basic silica gel, eluent:ethylacetate/methanol=100/0→90/10). The object fraction was concentratedunder reduced pressure and dried to give the title compound (36 mg) as awhite powder.

¹H-NMR (CDCl₃) δ 2.29 (3H, s), 2.54 (3H, s), 4.21 (2H, t, J=5.1 Hz),4.41 (2H, t, J=5.1 Hz), 6.59 (1H, d, J=2.7 Hz), 6.92 (1H, d, J=8.4 Hz),7.11 (1H, d, J=8.4 Hz), 7.18 (1H, dd, J=2.7, 8.4 Hz), 7.23-7.27 (2H, m),7.38 (1H, d, J=2.7 Hz), 8.26 (1H, d, J=2.7 Hz), 8.49 (1H, s).

Example 60

Production of ethyl 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino) benzoate

A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (2.78 g), ethyl3-aminobenzoate (4.49 g) and 1-methyl-2-pyrrolidone (20 mL) was stirredat 120° C. for 1.5 hrs. To the reaction mixture were added ethylacetate, water and saturated aqueous sodium hydrogen carbonate solution.The insoluble material was filtered off, and the ethyl acetate layer wasseparated. The aqueous layer was extracted with ethyl acetate, and themixed ethyl acetate layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The filtered insoluble material wassuspended in methanol and ethyl acetate and saturated brine were added.The ethyl acetate layer was separated. The ethyl acetate layer waswashed with saturated brine and dried over anhydrous magnesium sulfate.The mixed ethyl acetate layer was concentrated under reduced pressureand the obtained residue was purified by silica gel columnchromatography (eluent, ethyl acetate) and crystallized frommethanol-acetone-diisopropyl ether to give the title compound (2.85 g)as a pale-brown powder.

¹H-NMR (CDCl₃) δ: 1.39 (3H, t, J=7.2 Hz), 4.37 (2H, q, J=7.2 Hz), 6.51(1H, d, J=3.3 Hz), 7.28-7.32 (1H, m), 7.42 (1H, t, J=8.0 Hz), 7.70 (1H,d, J=7.8 Hz), 8.09 (1H, s), 8.29 (1H, d, J=8.1 Hz), 8.49 (1H, m).

Example 61

Production of 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid

A mixture of ethyl 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoate(3.34 g), 1N aqueous sodium hydroxide solution (25 mL) and methanol (50mL) was stirred overnight at room temperature. To the reaction mixturewas added 1N hydrochloric acid (25 mL), and methanol was evaporatedunder reduced pressure. The precipitated crystals were collected byfiltration and washed with water to give the title compound (3.09 g) asa pale-brown powder.

¹H-NMR (DMSO-d₆) δ: 6.50 (1H, m), 7.49 (1H, t, J=7.8 Hz), 7.60 (1H, d,J=7.8 Hz), 7.69 (1H, t, J=2.7 Hz), 8.25 (1H, d, J=7.8 Hz), 8.39 (1H, s),8.43 (1H, s), 9.54 (1H, s), 11.24 (1H, s), 13.01 (1H, br).

Example 62

Production ofN-[3-(piperidin-1-ylcarbonyl)phenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine

A mixture of 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid (153mg), piperidine (0.078 mL),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173 mg)and N,N-dimethylformamide (10 mL) was stirred at room temperature for 2hrs. Piperidine (0.078 mL) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173 mg)were added and the mixture was stirred for 1 hr. 1-Hydroxybenzotriazole(138 mg) was added, and the mixture was stirred for 3 days. Saturatedbrine was added to the reaction mixture and the mixture was extractedwith ethyl acetate. The extract was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the obtained residue was purified by silica gelcolumn chromatography (eluent, methanol:ethyl acetate=0:100→20:80).Diisopropyl ether was added and the precipitate was collected byfiltration to give the title compound (78 mg) as a pale-brown powder.

¹H-NMR (CDCl₃) δ: 1.56 (2H, m), 1.73 (4H, m), 3.42 (2H, m), 3.83 (2H,m), 6.58 (1H, d, J=2.4 Hz), 6.90 (1H, d, J=7.5 Hz), 7.18-7.22 (1H, m),7.23 (1H, s), 7.30 (1H, t, J=2.4 Hz), 7.88 (1H, d, J=8.3 Hz), 8.47 (1H,s), 8.70 (1H, s), 10.71 (1H, s).

Example 63

Production ofN-[3-(thiomorpholin-4-ylcarbonyl)phenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine

A mixture of 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid (153mg), thiomorpholine (0.091 mL),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173 mg)and N,N-dimethylformamide (10 mL) was stirred at room temperature for 2hrs. Thiomorpholine (0.030 mL) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173 mg)were added and the mixture was stirred for 1 hr. 1-Hydroxybenzotriazole(138 mg) was added, and the mixture was stirred for 3 days. Saturatedbrine was added to the reaction mixture and the mixture was extractedwith ethyl acetate. The extract was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the obtained residue was purified by silica gelcolumn chromatography (eluent, methanol:ethyl acetate=0:100→20:80).Diisopropyl ether was added and the precipitate was collected byfiltration. The precipitate was dissolved in ethyl acetate containingmethanol, washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, anddiisopropyl ether was added to the obtained residue and the precipitatewas collected by filtration to give the title compound (82 mg) as apale-brown powder.

¹H-NMR (CDCl₃) δ: 2.65 (2H, m), 2.77 (2H, m), 3.78 (2H, m), 4.05 (2H,m), 6.59 (1H, d, J=3.0 Hz), 6.98 (1H, d, J=6.9 Hz), 7.33 (1H, d, J=7.8Hz), 7.38 (1H, d, J=3.0 Hz), 7.53 (1H, s), 7.95 (1H, br), 8.48 (1H, s).

Example 64

Production ofN-{3-[(4-benzylpiperidin-1-yl)carbonyl]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

A mixture of 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid (153mg), 4-benzylpiperidine (158 mg),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173 mg),1-hydroxybenzotriazole (138 mg) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 3 hrs. The reaction mixture wasconcentrated under reduced pressure, water was added and extracted withethyl acetate containing tetrahydrofuran. The extract was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (eluent, methanol:ethylacetate=0:100→20:80). The obtained product was dissolved in ethylacetate containing methanol and tetrahydrofuran, washed with aqueoussodium hydrogen carbonate solution and saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and diisopropyl ether was added to the obtained residue. Theprecipitate was collected by filtration to give the title compound (201mg) as a pale-brown powder.

¹H-NMR (CDCl₃) δ: 1.10-2.00 (6H, m), 2.86 (2H, d, J=6.9 Hz), 2.75-3.05(2H, m), 3.78-3.91 (1H, m), 4.68-4.82 (1H, m), 6.55 (1H, d, J=3.0 Hz),6.90 (1H, d, J=7.5 Hz), 7.10-7.33 (7H, m), 7.40 (1H, s), 7.72 (1H, d,J=8.1 Hz), 8.45 (1H, s), 8.77 (1H, s), 10.83 (1H, s).

Example 65

Production of N-benzyl-3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzamide

A mixture of 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid (153mg), benzylamine (96 mg),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173 mg),1-hydroxybenzotriazole (138 mg) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 3 days. The reaction mixture wasconcentrated under reduced pressure, water was added and the mixture wasextracted with ethyl acetate containing tetrahydrofuran. The extract waswashed with saturated aqueous sodium hydrogen carbonate solution andsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (eluent, methanol:ethylacetate=0:100→50:50). Ethyl acetate and diethyl ether were added and theprecipitate was collected by filtration to give the title compound (128mg) as a colorless powder.

¹H-NMR (DMSO-d₆) δ: 4.50 (2H, d, J=6.0 Hz), 6.49 (1H, m), 7.21-7.38 (5H,m), 7.46 (1H, t, J=8.0 Hz), 7.55 (1H, d, J=8.1 Hz), 7.68 (1H, t, J=3.0Hz), 8.19 (1H, s), 8.26 (1H, d, J=8.0 Hz), 8.37 (1H, s), 9.06 (1H, t,J=6.0 Hz), 9.41 (1H, s), 11.13 (1H, s).

Example 66

Production of[2-(benzyloxy)-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)phenyl]methanol

A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (307 mg),[5-amino-2-(benzyloxy)phenyl]methanol (459 mg) and N,N-dimethylformamide(10 mL) was stirred at 80° C. for 4 hrs. The reaction mixture wasconcentrated under reduced pressure, aqueous sodium hydrogen carbonatesolution was added and the mixture was extracted with ethyl acetatecontaining tetrahydrofuran. The extract was washed with saturated brineand dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the obtained residue was purified by silicagel column chromatography (eluent, methanol:ethyl acetate=0:100→30:70).Ethanol and ethyl acetate were added and the precipitate was collectedby filtration to give the title compound (279 mg) as a brown powder.

¹H-NMR (DMSO-d₆) δ: 4.60 (2H, d, J=5.5 Hz), 5.12 (2H, s), 5.17 (1H, t,J=5.5 Hz), 6.45 (1H, m), 7.03 (1H, d, J=8.8 Hz), 7.29-7.51 (5H, m), 7.62(1H, t, J=2.9 Hz), 7.65 (1H, d, J=2.7 Hz), 7.93 (1H, dd, J=8.8, 2.7 Hz),8.29 (1H, s), 9.08 (1H, s), 11.05 (1H, s).

Example 67

Production ofN-[4-(benzyloxy)-3-methoxyphenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine

A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg),4-(benzyloxy)-3-methoxyaniline (298 mg) and 1-methyl-2-pyrrolidone (5mL) was stirred at 80° C. for 4 hrs. Methanol and activated carbon wereadded to the reaction mixture and the mixture was stirred. The activatedcarbon was filtered off, aqueous sodium hydrogen carbonate solution wasadded and the mixture was extracted with ethyl acetate. The extract waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the obtainedresidue was purified by silica gel column chromatography (eluent,methanol:ethyl acetate=10:80→20:80) and recrystallized frommethanol-ethyl acetate to give the title compound (269 mg) as apale-gray powder.

¹H-NMR (DMSO-d₆) δ: 3.82 (3H, s), 5.06 (2H, s), 6.45 (1H, m), 7.03 (1H,d, J=8.9 Hz), 7.30-7.49 (6H, m), 7.51 (1H, d, J=2.5 Hz), 7.63 (1H, t,J=2.9 Hz), 8.30 (1H, s), 9.07 (1H, s), 11.06 (1H, s).

Example 68

Production ofN-[4-(benzyloxy)-3-chlorophenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine

A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg),4-(benzyloxy)-3-chloroaniline (365 mg) and 1-methyl-2-pyrrolidone (3 mL)was stirred at 80° C. for 4 hrs. Methanol and activated carbon wereadded to the reaction mixture and the mixture was stirred. The activatedcarbon was filtered off, aqueous sodium hydrogen carbonate solution wasadded and the mixture was extracted with ethyl acetate. The extract waswashed with water and saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(eluent, methanol:ethyl acetate=0:100→15:75) and recrystallized fromethanol-ethyl acetate to give the title compound (226 mg) as apale-brown powder.

¹H-NMR (CDCl₃) δ: 5.15 (2H, s), 6.56 (1H, s), 6.98 (1H, d, J=8.9 Hz),7.28-7.43 (4H, m), 7.48 (2H, d, J=7.5 Hz), 7.69 (1H, d, J=8.9 Hz), 7.80(1H, d, J=2.6 Hz), 8.50 (1H, s), 8.63 (1H, s), 10.56 (1H, s).

Example 69

Production of ethyl2-phenoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoate

A mixture of ethyl 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (461 mg),5-amino-2-phenoxybenzoate (926 mg) and 1-methyl-2-pyrrolidone (5 mL) wasstirred at 80° C. for 2 hrs. Ethanol, water and activated carbon wereadded to the reaction mixture and the mixture was stirred. The activatedcarbon was filtered off, and the solvent was evaporated under reducedpressure. Aqueous sodium hydrogen carbonate solution was added to theresidue and the mixture was extracted with ethyl acetate. The extractwas washed with water and saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the obtained residue was purified by silica gel columnchromatography (eluent, methanol:ethyl acetate=0:100→20:80) andrecrystallized from ethanol-ethyl acetate to give the title compound(572 mg) as a colorless powder.

¹H-NMR (CDCl₃) δ: 1.12 (3H, t, J=7.1 Hz), 4.19 (2H, q, J=7.1 Hz), 6.57(1H, d, J=3.0 Hz), 6.84 (2H, d, J=7.7 Hz), 6.95 (1H, d, J=8.9 Hz), 7.00(1H, t, J=7.3 Hz), 7.19-7.29 (2H, m), 7.34 (1H, d, J=3.0 Hz), 7.80 (1H,dd, J=8.9, 2.8 Hz), 8.00 (1H, d, J=2.8 Hz), 8.67 (1H, s), 8.87 (1H, s),10.89 (1H, s).

Example 70

Production of 2-phenoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoicacid

A mixture of ethyl2-phenoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoate (899 mg), 1Naqueous sodium hydroxide solution (5 mL) and methanol (15 mL) wasstirred at 60° C. for 1.5 hrs. To the reaction mixture was added 1Nhydrochloric acid (5 mL), and methanol was evaporated under reducedpressure. The precipitated crystals were collected by filtration, andwashed with water and acetone to give the title compound (768 mg) as apale-brown powder.

¹H-NMR (DMSO-d₆) δ: 6.50 (1H, m), 6.89 (2H, d, J=7.7 Hz), 7.04 (1H, t,J=7.3 Hz), 7.12 (1H, d, J=8.9 Hz), 7.33 (2H, t, J=8.0 Hz), 7.69 (1H, t,J=2.9 Hz), 8.16 (1H, dd, J=8.9, 2.9 Hz), 8.31 (1H, d, J=2.9 Hz), 8.37(1H, s), 9.46 (1H, s), 11.11 (1H, s), 12.95 (1H, br).

Example 71

Production of[2-phenoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)phenyl]methanol

To a solution of2-phenoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid (173 mg)in N,N-dimethylformamide (5 mL) was added 1,1′-carbonyldiimidazole (97mg) and the mixture was stirred at room temperature for 1 hr. Sodiumborohydride (38 mg) was added to the reaction mixture at roomtemperature, and methanol (1 mL) was added dropwise. After stirringovernight at room temperature, water was added to the reaction mixtureand the mixture was extracted with ethyl acetate. The extract was washedwith water and saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(eluent, methanol:ethyl acetate=0:100→20:80) and crystallized frommethanol-ethyl acetate, to give the title compound (44 mg) as acolorless powder.

¹H-NMR (DMSO-d₆) δ: 4.50 (2H, d, J=5.1 Hz), 5.28 (1H, t, J=255.1 Hz),6.48 (1H, m), 6.90 (2H, d, J=7.7 Hz), 6.96 (1H, d, J=8.7 Hz), 7.06 (1H,t, J=7.3 Hz), 7.30-7.40 (2H, m), 7.66 (1H, t, J=2.9 Hz), 7.85 (1H, d,J=2.7 Hz), 8.04 (1H, dd, J=8.7, 2.7 Hz), 8.34 (1H, s), 9.28 (1H, s),11.11 (1H, s).

Example 72

Production of6-(2-furyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production of 2-cyano-1-(2-furyl)vinyl 4-methylbenzenesulfonate

To a mixture of 3-(2-furyl)-3-oxopropanenitrile (5.29 g),p-toluenesulfonyl chloride (9.00 g) and dichloromethane (60 mL) wasadded dropwise triethylamine (5.99 g) under ice-cooling. After stirringunder ice-cooling for 1.5 hrs, the mixture was diluted withdichloromethane (100 mL). The mixture was washed with water (150 mL),dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent, hexane:methyl acetate=9:1→3:1) to give the title compound(10.48 g) as a mixture of (E)-form and (Z)-form (3:1).

¹H-NMR (CDCl₃) δ 2.47 (3/4H, s), 2.49 (9/4H, s), 5.27 (1/4H, s), 5.63(3/4H, s), 6.47 (1/4H, m), 6.53 (3/4H, m), 6.86 (1/4H, d, J=3.6 Hz),6.95 (3/4H, d, J=3.6 Hz), 7.38 (1/2H, d, J=7.8 Hz), 7.42 (3/2H, d, J=7.8Hz), 7.51 (3/4H, m), 7.55 (1/4H, m), 7.83 (1/2H, d, J=7.8 Hz), 7.97(3/2H, d, J=7.8 Hz).

(ii) Production of ethyl 3-amino-5-(2-furyl)-1H-pyrrole-2-carboxylate

To a solution of 2-cyano-1-(2-furyl)vinyl 4-methylbenzenesulfonate(10.48 g) and diethyl aminomalonate hydrochloride (7.67 g) in a mixedsolvent of ethanol (120 mL)-tetrahydrofuran (64 mL) was added dropwise asolution (36.9 mL) of 20% sodium ethoxide in ethanol under ice-cooling.After stirring at room temperature for 12 hrs, the reaction mixture waspoured into ice water (350 mL) and adjusted to pH 7 with 1N hydrochloricacid. The organic solvent was evaporated under reduced pressure, and theresidue was extracted with ethyl acetate (150 mL×3). The organic layerswere combined, washed with saturated brine (100 mL), and dried overanhydrous magnesium sulfate. After concentration under reduced pressure,the residue was purified by silica gel column chromatography (eluent,hexane:methyl acetate=3:1→1:1) and the obtained solid was recrystallizedfrom ethyl acetate-hexane to give the title compound (2.66 g).

¹H-NMR (CDCl₃) δ 1.37 (3H, t, J=7.0 Hz), 4.34 (2H, q, J=7.0 Hz), 4.37(2H, br s), 5.93 (1H, d, J=2.7 Hz), 6.45 (1H, dd, J=3.6, 1.8 Hz), 6.49(1H, d, J=3.6 Hz), 7.41 (1H, d, J=1.8 Hz), 8.35 (1H, br s).

(iii) Production of6-(2-furyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one

To a solution of ethyl 3-amino-5-(2-furyl)-1H-pyrrole-2-carboxylate(2.58 g) in ethanol (35 mL) was added formamidine acetate (1.83 g), andthe mixture was heated under reflux for 18 hrs. After cooling to roomtemperature, the precipitated solid was collected by filtration, washedwith ethanol, and dried under reduced pressure at 60° C. to give thetitle compound (2.26 g).

¹H-NMR (DMSO-d₆) δ 6.58 (1H, d, J=2.1 Hz), 6.61 (1H, dd, J=3.5, 2.1 Hz),7.08 (1H, m), 7.76 (1H, m), 7.80 (1H, d, J=3.5 Hz), 11.91 (1H, br s),12.50 (1H, br s).

(iv) Production of 4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine

A mixture of 6-(2-furyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one(2.20 g) and phosphoryl chloride (10.7 g) was stirred at 100° C. for 20min, dioxane (30 mL) was added, and the mixture was stirred at 100° C.for 3 hrs. After concentration under reduced pressure, saturated aqueoussodium hydrogen carbonate was added to the residue, and the mixture wasextracted with ethyl acetate-acetone (155 mL×4). The organic layers werecombined, washed with saturated brine (100 mL), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas washed with ethyl acetate-diethyl ether, and dried under reducedpressure at 60° C. to give the title compound (2.19 g).

¹H-NMR (DMSO-d₆) δ 6.74 (1H, dd, J=3.6, 2.1 Hz), 6.95 (1H, d, J=1.8 Hz),7.37 (1H, dd, J=3.6, 0.6 Hz), 7.95 (1H, dd, J=2.1, 0.6 Hz), 8.60 (1H,s), 12.71 (1H, br s).

(v) Production of6-(2-furyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

A mixture of 4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (110 mg),3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (161 mg) and1-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140° C. for 2 hrs,poured into water (10 mL) and adjusted to pH 8 with saturated aqueoussodium hydrogen carbonate. The mixture was extracted with ethyl acetate(25 mLx2) and the organic layers were combined and dried over anhydrousmagnesium sulfate. After concentration under reduced pressure, theresidue was subjected to silica gel column chromatography (eluent,hexane:ethyl acetate=1:1→0:1). The object fraction was concentratedunder reduced pressure. Chloroform—diisopropyl ether was added to theresidue, and the solid was collected by filtration and dried underreduced pressure at 60° C. to give the title compound (114 mg).

¹H-NMR (DMSO-d₆) δ 2.21 (3H, s), 2.48 (3H, s), 6.72 (1H, dd, J=3.3, 1.8Hz), 6.78 (1H, d, J=1.8 Hz), 6.98 (1H, d, J=8.4 Hz), 7.02 (1H, d, J=3.6Hz), 7.17 (1H, dd, J=8.4, 2.7 Hz), 7.22 (1H, d, J=8.4 Hz), 7.74 (1H, dd,J=8.4, 2.7 Hz), 7.80 (1H, d, J=2.1 Hz), 7.92 (1H, dd, J=1.8, 0.9 Hz),8.16 (1H, dd, J=2.7, 0.9 Hz), 8.33 (1H, s), 9.17 (1H, br s), 11.67 (1H,br s).

Example 73

Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

A mixture of 4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (110 mg),3-chloro-4-[(3-fluorobenzyl)oxy]aniline (189 mg) and1-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140° C. for 2 hrs,poured into water (10 mL) and adjusted to pH 8 with saturated aqueoussodium hydrogen carbonate. The mixture was extracted with ethyl acetate(30 mL×2). The organic layers were combined and dried over anhydrousmagnesium sulfate. After concentration under reduced pressure, theresidue was subjected to silica gel column chromatography (eluent,hexane:ethyl acetate=4:1→1:1). The object fraction was concentratedunder reduced pressure. Chloroform—diisopropyl ether was added to theresidue, and the solid was collected by filtration and dried underreduced pressure at 60° C. to give the title compound (122 mg).

¹H-NMR (DMSO-d₆) δ 5.23 (2H, s), 6.71 (1H, dd, J=3.3, 2.1 Hz), 6.78 (1H,d, J=2.1 Hz), 7.02 (1H, d, J=3.3 Hz), 7.18 (1H, m), 7.25 (1H, d, J=9.0Hz), 7.28-7.33 (2H, m), 7.46 (1H, m), 7.57 (1H, dd, J=9.0, 3.0 Hz), 7.92(1H, d, J=1.8 Hz), 8.18 (1H, d, J=2.4 Hz), 8.33 (1H, s), 9.18 (1H, brs), 11.61 (1H, br s).

Example 74

Production ofN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

A mixture of 4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (80 mg),3-chloro-4-(pyridin-2-ylmethoxy)aniline (94 mg) and1-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140° C. for 2 hrs,poured into water (10 mL) and adjusted to pH 8 with saturated aqueoussodium hydrogen carbonate. The mixture was extracted with ethyl acetate(30 mL×2). The organic layers were combined and dried over anhydrousmagnesium sulfate. After concentration under reduced pressure, theresidue was subjected to silica gel column chromatography (eluent,hexane:ethyl acetate=1:1→0:1). The object fraction was concentratedunder reduced pressure. Chloroform—diisopropyl ether was added to theresidue, and the solid was collected by filtration and dried underreduced pressure at 60° C. to give the title compound (71 mg).

¹H-NMR (DMSO-d₆) δ 5.27 (2H, s), 6.72 (1H, m), 6.78 (1H, d, J=1.2 Hz),7.02 (1H, d, J=3.3 Hz), 7.26 (1H, d, J=9.0 Hz), 7.36 (1H, m), 7.53-7.59(2H, m), 7.81 (1H, d, J=8.1 Hz), 7.91 (1H, s), 8.21 (1H, d, J=2.4 Hz),8.34 (1H, s), 8.59 (1H, d, J=5.1 Hz), 9.19 (1H, br s), 11.62 (1H, br s).

Example 75

Production of4-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]benzoicacid hydrochloride (i) Production of methyl4-(2-cyano-1-{[(4-methylphenyl)sulfonyl]oxy}vinyl)benzoate

To a mixture of methyl 4-(cyanoacetyl)benzoate (10.29 g),p-toluenesulfonyl chloride (11.58 g) and dichloromethane (110 mL) wasadded dropwise triethylamine (7.68 g) under ice-cooling. After stirringunder ice-cooling for 2.5 hrs, the mixture was diluted withdichloromethane (100 mL), washed with water (150 mL), dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent,hexane:methyl acetate=9:1→1:1) to give the title compound (17.60 g) as amixture of (E)-form and (Z)-form (6:5).

¹H-NMR (CDCl₃) δ 2.44 (18/11H, s), 2.47 (15/11H, s), 3.94 (18/11H, s),3.95 (15/11H, s), 5.66 (6/11H, s), 5.68 (5/11H, s), 7.33 (12/11H, d,J=7.8 Hz), 7.38 (10/11H, d, J=7.8 Hz), 7.62-8.09 (6H, m).

(ii) Production of ethyl3-amino-5-[4-(ethoxycarbonyl)phenyl]-1H-pyrrole-2-carboxylate

To a suspension of methyl4-(2-cyano-1-{[(4-methylphenyl)sulfonyl]oxy}vinyl)benzoate (17.5 g) anddiethyl aminomalonate hydrochloride (10.36 g) in a mixed solvent ofethanol (165 mL)-tetrahydrofuran (80 mL) was added dropwise a solution(50 mL) of 20% sodium ethoxide in ethanol under ice-cooling. Afterstirring under ice-cooling for 1 hr, the mixture was stirred at roomtemperature for 21 hr. the reaction mixture was poured into ice water(400 mL) and adjusted to pH 7 with 1N hydrochloric acid. The organicsolvent was evaporated under reduced pressure, and the residue wasextracted with ethyl acetate (250 mL×3). The organic layers werecombined, washed with saturated brine (150 mL), and dried over anhydrousmagnesium sulfate. After concentration under reduced pressure, theresidue was purified by silica gel column chromatography (eluent,hexane:ethyl acetate=2:1→1:1) and the obtained solid was recrystallizedfrom ethyl acetate to give the title compound (4.76 g).

¹H-NMR (CDCl₃) δ 1.36-1.43 (6H, m), 4.31-4.42 (6H, m), 6.11 (1H, d,J=3.0 Hz), 7.55 (2H, d, J=8.4 Hz), 8.04 (2H, d, J=8.4 Hz), 8.40 (1H, brs).

(iii) Production of ethyl4-(4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl)benzoate

A mixture of ethyl3-amino-5-[4-(ethoxycarbonyl)phenyl]-1H-pyrrole-2-carboxylate (3.36 g),formamidine acetate (1.74 g) and ethanol (60 mL) was heated under refluxfor 15 hrs. After cooling to room temperature, the precipitated solidwas collected by filtration, washed with ethanol, and dried underreduced pressure at 60° C. to give the title compound (2.97 g).

¹H-NMR (DMSO-d₆) δ 1.34 (3H, t, J=7.1 Hz), 4.33 (2H, q, J=7.1 Hz), 7.04(1H, s), 7.84 (1H, d, J=2.7 Hz), 8.00 (2H, d, J=8.1 Hz), 8.11 (2H, d,J=8.1 Hz), 11.97 (1H, br s), 12.64 (1H, br s).

(iv) Production of ethyl4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-yl)benzoate hydrochloride

A mixture of ethyl4-(4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl)benzoate (2.97 g)and phosphoryl chloride (16.45 g) was stirred at 110° C. for 1 hr,dioxane (10 mL) was added and the mixture was heated under reflux for 4hrs. After concentration under reduced pressure, ethanol (30 mL) wasadded to the residue and, after stirring at room temperature for 30 min,the precipitated solid was collected by filtration. The solid was washedwith ethanol and dried under reduced pressure at 60° C. to give thetitle compound (3.34 g).

¹H-NMR (DMSO-d₆) δ 1.36 (3H, d, J=7.1 Hz), 4.36 (2H, q, J=7.1 Hz), 7.40(1H, s), 8.09 (2H, d, J=8.7 Hz), 8.26 (2H, d, J=8.7 Hz), 8.67 (1H, s),12.77 (1H, br s).

(v) Production of4-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]benzoicacid hydrochloride

A mixture of ethyl 4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-yl)benzoatehydrochloride (1.297 g), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline(1.00 g), diisopropylethylamine (0.834 g) and 1-methyl-2-pyrrolidinone(12.5 mL) was stirred at 140° C. for 3 hrs, poured into water (100mL)-ethyl acetate (150 mL) and the precipitated solid was collected byfiltration. The solid was washed with ethyl acetate and dried underreduced pressure at 60° C. The obtained solid was suspended in methanol(40 mL), and 1N aqueous sodium hydroxide solution (20 mL) was added.After stirring at room temperature for 12 hrs, the solvent wasevaporated under reduced pressure, and the residue was adjusted to pH 2with 1N hydrochloric acid. The precipitated solid was collected byfiltration, washed with water and dried under reduced pressure at 60° C.to give the title compound (1.08 g).

¹H-NMR (DMSO-d₆) δ 2.21 (3H, s), 2.44 (3H, s), 6.98 (1H, d, J=9.0 Hz),7.15 (1H, s), 7.17-7.25 (2H, m), 7.76 (1H, d, J=8.7 Hz), 7.85 (1H, s),8.01-8.17 (5H, m), 8.48 (1H, s), 9.99 (1H, br s), 12.47 (1H, br s).

Example 76

Production of4-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]benzoicacid hydrochloride

A mixture of ethyl 4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-yl)benzoatehydrochloride (517 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (462 mg)and 1-methyl-2-pyrrolidinone (8 mL) was stirred at 140° C. for 5 hrs,poured into water (40 mL), and adjusted to pH 8 with saturated aqueoussodium hydrogen carbonate. The precipitated solid was collected byfiltration, washed with water and suspended in methanol (15 mL). Afterstirring at room temperature for 30 min, the solid was collected byfiltration and dried under reduced pressure at 60° C. The obtained solidwas suspended in ethanol (10 mL) and 1N aqueous sodium hydroxidesolution (1.5 mL) was added. After stirring at room temperature for 6.5hrs, and at 60° C. for 3.5 hrs, the mixture was cooled to roomtemperature. 1N Hydrochloric acid (155 mL) was added, and theprecipitated solid was collected by filtration, washed with water anddried under reduced pressure at 60° C. to give the title compound (498mg).

¹H-NMR (DMSO-d₆) δ 5.24 (2H, s), 7.12-7.35 (5H, m), 7.48 (1H, m), 7.70(1H, d, J=8.7 Hz), 8.01-8.12 (4H, m), 8.27 (1H, s), 8.37 (1H, s), 9.65(1H, br s), 12.15 (1H, br s).

Example 77

Production of6-(2-furyl)-5-methyl-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production of4-chloro-6-(2-furyl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine

To a solution of 4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (220mg) in N,N-dimethylformamide (2.5 mL) were added potassium carbonate(139 mg) and methyl iodide (0.25 mL) and the mixture was stirred at roomtemperature for 8 hrs. The mixture was poured into water (30 mL) andextracted with ethyl acetate (30 mL×3). The organic layers were combinedand dried over anhydrous magnesium sulfate. After concentration underreduced pressure, the residue was subjected to silica gel columnchromatography (eluent, hexane:ethyl acetate=4:1→0:1) to give the titlecompound (94 mg).

¹H-NMR (CDCl₃) δ 4.29 (3H, s), 6.62 (1H, dd, J=3.6, 1.8 Hz), 6.86 (1H,d, J=3.6 Hz), 6.94 (1H, s), 7.67 (1H, d, J=1.8 Hz), 8.68 (1H, s).

(ii) Production of6-(2-furyl)-5-methyl-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

A mixture of 4-chloro-6-(2-furyl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine(92 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (102 mg) and1-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140° C. for 3.5 hrs,poured into water (10 mL) and adjusted to pH 8 with saturated aqueoussodium hydrogen carbonate. The mixture was extracted with ethyl acetate(25 mL×2), and the organic layers were combined and dried over anhydrousmagnesium sulfate. After concentration under reduced pressure, theresidue was subjected to silica gel column chromatography (eluent,hexane:ethyl acetate=1:1→0:1). The object fraction was concentratedunder reduced pressure. Diethyl ether was added to the residue, and thesolid was collected by filtration and dried under reduced pressure at60° C. to give the title compound (105 mg).

¹H-NMR (DMSO-d₆) δ 2.17 (3H, s), 2.43 (3H, s), 4.12 (3H, s), 6.74 (1H,dd, J=3.6, 1.2 Hz), 6.76 (1H, s), 6.93 (1H, d, J=8.7 Hz), 7.05 (1H, d,J=3.6 Hz), 7.17 (1H, dd, J=8.7, 2.4 Hz), 7.23 (1H, d, J=8.7 Hz), 7.46(1H, dd, J=8.7, 3.0 Hz), 7.52 (1H, d, J=2.4 Hz), 7.94 (1H, d, J=1.2 Hz),8.16 (1H, d, J=3.0 Hz), 8.27 (1H, s), 8.71 (1H, br s).

Example 78

Production of5-(2-ethoxyethyl)-6-(2-furyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production of4-chloro-5-(2-ethoxyethyl)-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine

To a solution of 4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (220mg) in N,N-dimethylformamide (1.2 mL) was added cesium carbonate (489mg) under ice-cooling, and the mixture was stirred under ice-cooling for15 min. 2-Bromoethyl ethyl ether (0.169 mL) was added and the mixturewas stirred at room temperature for 2 days. Cesium carbonate (326 mg)and 2-bromoethyl ethyl ether (0.113 mL) were added and the mixture wasstirred at room temperature for 1 day. The reaction mixture was pouredinto water (30 mL) and extracted with ethyl acetate (60 mL). The organiclayer was dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was subjected to silica gel columnchromatography (eluent, hexane:ethyl acetate=4:1→1:4) to give the titlecompound (76 mg).

¹H-NMR (CDCl₃) δ 1.09 (3H, t, J=6.9 Hz), 3.42 (2H, q, J=6.9 Hz), 3.82(2H, t, J=6.3 Hz), 4.92 (2H, t, J=6.3 Hz), 6.60 (1H, dd, J=3.6, 2.1 Hz),6.94 (1H, s), 6.98 (1H, d, J=3.6 Hz), 7.64 (1H, d, J=2.1 Hz), 8.68 (1H,s).

(ii) Production of5-(2-ethoxyethyl)-6-(2-furyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

A mixture of4-chloro-5-(2-ethoxyethyl)-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (76mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (67 mg) and1-methyl-2-pyrrolidinone (1.5 mL) was stirred at 140° C. for 2 hrs,poured into water (8 mL) and adjusted to pH 8 with saturated aqueoussodium hydrogen carbonate. The mixture was extracted with ethyl acetate(20 mL×2) and the organic layers were combined and dried over anhydrousmagnesium sulfate. After concentration under reduced pressure, theresidue was subjected to silica gel column chromatography (eluent,hexane:ethyl acetate=1:1→0:1). The object fraction was concentratedunder reduced pressure. Diisopropyl ether-hexane was added to theresidue, and the solid was collected by filtration and dried underreduced pressure at 60° C. to give the title compound (78 mg).

¹H-NMR (DMSO-d₆) δ 1.08 (3H, t, J=6.9 Hz), 2.18 (3H, s), 2.43 (3H, s),3.52 (2H, q, J=6.9 Hz), 3.95 (2H, t, J=4.4 Hz), 4.68 (2H, brt, J=4.4Hz), 6.73 (1H, dd, J=3.6, 1.8 Hz), 6.84 (1H, s), 6.96 (1H, d, J=8.1 Hz),7.01 (1H, d, J=3.6 Hz), 7.16 (1H, dd, J=8.4, 2.7 Hz), 7.22 (1H, d, J=8.4Hz), 7.50-7.55 (2H, m), 7.93 (1H, d, J=1.8,Hz), 8.15 (1H, d, J=2.7 Hz),8.31 (1H, s), 9.15 (1H, br s).

Example 79

Production of{4-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]phenyl}methanol

To a suspension of4-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]benzoicacid (122 mg) in tetrahydrofuran (10 mL) was added triethylamine (30.5mg) and, after stirring at room temperature for 10 min,1,1′-carbonyldiimidazole (49 mg) was added, and the mixture was stirredat room temperature for 13 hrs. Under ice-cooling, sodium borohydride(28 mg) was added, and methanol (2.5 mL) was further added. Afterstirring under ice-cooling for 2 hrs, water (1.5 mL) was added, andtetrahydrofuran and methanol were evaporated under reduced pressure.Water (20 mL) was added, and the mixture was extracted with ethylacetate (30 mL)-tetrahydrofuran (15 mL). The organic layer wasseparated, and the aqueous layer was extracted with ethyl acetate (15mL)-tetrahydrofuran (5 mL). The organic layers were combined and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was subjected to silica gel column chromatography(eluent, ethyl acetate:methanol=99:1→9:1). The object fraction wasconcentrated under reduced pressure. The residue was recrystallized frommethanol-ethyl acetate to give the title compound (65 mg).

¹H-NMR (DMSO-d₆) δ 2.21 (3H, s), 2.43 (3H, s), 4.57 (2H, d, J=4.8 Hz),5.32 (1H, brt, J=4.8 Hz), 6.96 (1H, s), 6.99 (1H, d, J=8.4 Hz), 7.18(1H, dd, J=8.7, 2.7 Hz), 7.23 (1H, d, J=8.7 Hz), 7.50 (2H, d, J=7.8 Hz),7.74 (1H, dd, J=8.4, 2.7 Hz), 7.81-7.85 (3H, m), 8.16 (1H, d, J=2.7 Hz),8.34 (1H, s), 9.09 (1H, br s), 11.56 (1H, br s).

Example 80

Production ofN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-6-[4-({[2-(methylsulfonyl)ethyl]amino}methyl)phenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine

A mixture of{4-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]phenyl}methanol(96 mg), manganese dioxide (1.0 g) and N,N-dimethylformamide (5 mL) wasstirred at room temperature for 12 hrs. After celite filtration, thefiltrate was concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography (eluent, ethylacetate:methanol=100:0→9:1). A mixture of the obtained solid,methylsulfonylethylamine hydrochloride (27.5 mg), N,N-dimethylformamide(2 mL) and acetic acid (0.02 mL) was stirred at room temperature for 1hr, and sodium triacetoxyborohydride (36.6 mg) was added. After stirringat room temperature for 4.5 hrs, saturated aqueous sodium hydrogencarbonate (10 mL) was added, and the mixture was extracted with ethylacetate (25 mL×2). The organic layers were combined, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was subjected to silica gel column chromatography (ethylacetate:methanol=10:0→9:1). The object fraction was concentrated underreduced pressure. Chloroform—diisopropyl ether was added to the residue,and the solid was collected by filtration and dried under reducedpressure at 60° C. to give the title compound (28 mg).

¹H-NMR (DMSO-d₆) δ 2.21 (3H, s), 2.44 (3H, s), 2.94 (2H, t, J=6.6 Hz),3.00 (3H, s), 3.29 (2H, t, J=6.6 Hz), 3.78 (2H, s), 6.97 (1H, s), 7.00(1H, d, J=8.7 Hz), 7.19 (1H, dd, J=8.4, 2.7 Hz), 7.24 (1H, d, J=8.4 Hz),7.51 (2H, d, J=8.4 Hz), 7.77 (1H, dd, J=8.7, 2.4 Hz), 7.83-7.87 (3H, m),8.18 (1H, d, J=2.4 Hz), 8.34 (1H, s), 9.23 (1H, br s), 11.73 (1H, br s).

Example 81

Production of6-(aminomethyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (i) Production ofN4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodopyrimidine-4,5-diamine

A solution of 5-amino-4,6-diiodopyrimidine (3.83 g) and3-chloro-4-[(3-fluorobenzyl)oxy]aniline (2.78 g) in1-methyl-2-pyrrolidone (30 mL) was stirred at 70° C. for 14 hrs. Waterwas added to the reaction system and the mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine and dried over magnesium sulfate. After concentration underreduced pressure, the residue was separated and purified by columnchromatography (eluent, ethyl acetate:hexane=1:4→2:3→1:1) to give thetitle compound (4.21 g) as brown powder crystals.

¹H-NMR (CDCl₃) δ: 3.47 (2H, br s), 5.13 (2H, s), 6.73 (1H, br s), 6.92(1H, d, J=9.0 Hz), 6.96-7.04 (1H, m), 7.15-7.25 (2H, m), 7.31-7.38 (2H,m), 7.64 (1H, d, J=2.7 Hz), 8.04 (1H, s).

(ii) Production of tert-butyl3-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrimidin-4-yl]prop-2-ynylcarbamate

To a solution ofN4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodopyrimidine-4,5-diamine(0.84 g) and tert-butyl prop-2-ynylcarbamae (0.36 g) inacetonitrile-triethylamine (20 mL-15 mL) were addedbis(triphenylphosphine)palladium(II) dichloride (62.5 mg) and copper(I)iodide (20.3 mg) at room temperature, and the mixture was stirred atroom temperature under an argon atmosphere for 6 hrs. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (eluent, ethylacetate:hexane=1:1→ethyl acetate) to give the title compound (766.5 mg)as a brown solid.

¹H-NMR (DMSO-d₆) δ: 1.42 (9H, s), 4.06 (2H, d, J=5.4 Hz), 5.22 (2H, s),5.45 (2H, br s), 7.13-7.23 (2H, m), 7.26-7.34 (2H, m), 7.42-7.51 (2H,m), 7.54-7.60 (1H, m), 7.95 (2H, s), 8.54 (1H, s).

(iii) Production of tert-butyl[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]methylcarbamate

A mixture of tert-butyl(3-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrimidin-4-yl]prop-2-ynylcarbamate(720 mg) and copper(I) iodide (55.2 mg) in N,N-dimethylformamide (7.0mL) was stirred at 80° C. for 12 hrs. After concentration under reducedpressure, the residue was separated and purified by columnchromatography (basic silica gel, eluent, ethyl acetate→methanol:ethylacetate=1:9) to give the title compound (604 mg) as pale-yellow powdercrystals.

¹H-NMR (DMSO-d₆) δ: 1.42 (9H, s), 4.33 (2H, d, J=5.7 Hz), 5.22 (2H, s),6.29 (1H, s), 7.14-7.35 (4H, m), 7.41-7.60 (3H, m), 8.16 (1H, d, J=2.7Hz), 8.30 (1H, s), 9.29 (1H, s), 10.96 (1H, br s).

(iv) Production of6-(aminomethyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride

To a solution of tert-butyl[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]methylcarbamate(500 mg) in tetrahydrofuran (12 mL) was added 2N hydrochloric acid (6.0mL) at room temperature. The mixture was stirred at 60° C. for 2 hrs,ethanol was added to the reaction system and the mixture wasconcentrated under reduced pressure. The resultant crystals werecollected by filtration and washed with diisopropyl ether to give thetitle compound (481.4 mg) as pale-yellow powder crystals.

¹H-NMR (DMSO-d₆) δ: 4.28-4.39 (2H, m), 5.28 (2H, s), 6.89 (1H, s),7.15-7.25 (1H, m), 7.29-7.40 (3H, m), 7.45-7.54 (1H, m), 7.73-7.80 (1H,m), 8.15 (1H, s), 8.48-8.65 (3H, m), 8.82 (1H, s).

Example 82

Production of(2E)-N-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]methyl}-4-(dimethylamino)but-2-enamide

A solution of6-(aminomethyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (150 mg), (2E)-4-(dimethylamino)but-2-enoic acidhydrochloride (105 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (244 mg), 1-hydroxybenzotriazole monohydrate (196 mg) andtriethylamine (0.30 mL) in N,N-dimethylformamide (5 mL) was stirred atroom temperature for 2 days. Water was added to the reaction system andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over magnesium sulfate andconcentrated under reduced pressure, and the residue was separated andpurified by column chromatography (basic silica gel, eluent,methanol:ethyl acetate=1:9→1:4) to give the title compound (104.2 mg) aspale-brown powder crystals.

¹H-NMR (DMSO-d₆) δ: 2.14 (6H, s), 3.00 (2H, d, J=6.1 Hz), 4.54 (2H, d,J=5.7 Hz), 5.21 (2H, s), 6.11 (1H, d, J=15.3 Hz), 6.35 (1H, s), 6.66(1H, dt, J=15.3, 6.1 Hz), 7.12-7.34 (4H, m), 7.41-7.49 (1H, m),7.53-7.60 (1H, m), 8.14 (1H, d, J=2.4 Hz), 8.29 (1H, s), 8.69 (1H, t,J=5.7 Hz), 9.34 (1H, br s), 10.99 (1H, br s).

Example 83

Production of6-(3-aminophenyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production of6-[(3-aminophenyl)ethynyl]-N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}pyrimidine-4,5-diamine

The title compound (1.35 g) was obtained as brown powder crystals by thereaction in the same manner as in Example 81 (ii) usingN4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodopyrimidine-4,5-diamine(1.90 g), 3-aminophenylacetylene (0.41 mL),bis(triphenylphosphine)palladium(II) dichloride (102 mg), copper(I)iodide (27 mg), acetonitrile (24 mL) and triethylamine (18 mL).

¹H-NMR (CDCl₃) δ: 3.65-3.78 (4H, m), 5.15 (2H, s), 6.59 (1H, s), 6.73(1H, d, J=8.1 Hz), 6.90-7.06 (4H, m), 7.14-7.41 (5H, m), 7.68 (1H, d,J=2.7 Hz), 8.35 (1H, s).

(ii) Production of6-(3-aminophenyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

The title compound (673 mg) was obtained as brown powder crystals by thereaction in the same manner as in Example 81 (iii) using6-[(3-aminophenyl)ethynyl]-N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}pyrimidine-4,5-diamine(1.30 g), copper(I) iodide (54 mg) and N,N-dimethylformamide (7.0 mL).

¹H-NMR (DMSO-d₆) δ: 5.23 (2H, s), 5.31 (2H, s), 6.58-6.65 (1H, m), 6.75(1H, s), 6.94-7.01 (2H, m), 7.13-7.34 (5H, m), 7.43-7.50 (1H, m), 7.57(1H, dd, J=8.9, 2.6 Hz), 8.19 (1H, d, J=2.1 Hz), 8.32 (1H, s), 9.13 (1H,s), 11.40 (1H, s).

Example 84

Production ofN-{3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]phenyl}-2-methoxyacetamide

The title compound (42.9 mg) was obtained as pale-brown powder crystalsby the reaction in the same manner as in Example 82 using6-(3-aminophenyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(80 mg), methoxyacetic acid (31 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (67 mg),1-hydroxybenzotriazole monohydrate (54 mg), triethylamine (0.1 mL) andN,N-dimethylformamide (5 mL).

¹H-NMR (DMSO-d₆) δ: 3.42 (3H, s), 4.06 (2H, s), 5.24 (2H, s) 6.87 (1H,s), 7.13-7.36 (4H, m), 7.44-7.69 (5H, m), 8.19-8.26 (2H, m), 8.35 (1H,s), 9.25 (1H, s), 9.95 (1H, s), 11.56 (1H, s).

Example 85

Production of6-(4-aminophenyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production of6-[(4-aminophenyl)ethynyl]-N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}pyrimidine-4,5-diamine

The title compound (1.12 g) was obtained as a yellow solid by thereaction in the same manner as in Example 81 (ii) usingN4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodopyrimidine-4,5-diamine(1.50 g), 4-aminophenylacetylene (411 mg),bis(triphenylphosphine)palladium(II) dichloride (112 mg), copper(I)iodide (36.5 mg), acetonitrile (24 mL) and triethylamine (18 mL).

¹H-NMR (CDCl₃) δ: 3.68 (2H, br s), 3.94 (2H, br s), 5.14 (2H, s), 6.58(1H, br s), 6.65 (2H, d, J=7.8 Hz), 6.95 (1H, d, J=9.0 Hz), 6.96-7.06(1H, m), 7.19-7.43 (6H, m), 7.68 (1H, d, J=2.7 Hz), 8.34 (1H, s).

(ii) Production of6-(4-aminophenyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

The title compound (768.6 mg) was obtained as yellow powder crystals bythe reaction in the same manner as in Example 81 (iii) using6-[(4-aminophenyl)ethynyl]-N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}pyrimidine-4,5-diamine(1.11 g), copper(I) iodide (46 mg) and N,N-dimethylformamide (6.0 mL).

¹H-NMR (DMSO-d₆) δ: 5.22 (2H, s), 5.53 (2H, s), 6.65-6.70 (3H, m),7.12-7.35 (4H, m), 7.42-7.61 (4H, m), 8.17 (1H, d, J=2.7 Hz), 8.28 (1H,s), 8.99 (1H, s), 11.21 (1H, br s).

Example 86

Production ofN-{4-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]phenyl}-2-methoxyacetamide

A solution of6-(4-aminophenyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(100 mg), methoxyacetic acid (29.4 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (94 mg),1-hydroxybenzotriazole monohydrate (75 mg) and triethylamine (0.23 mL)in N,N-dimethylformamide (5 mL) was stirred at room temperature for 20hrs. Methoxyacetic acid (29.4 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (94 mg) and1-hydroxybenzotriazole monohydrate (75 mg) were added to the reactionsystem, and the mixture was further stirred for 24 hrs. Water was addedto the reaction system and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over magnesiumsulfate and concentrated under reduced pressure, and the residue wasseparated and purified by column chromatography (basic silica gel,eluent, ethyl acetate→methanol:ethyl acetate=14:85) to give the titlecompound (63.5 mg) as pale-brown powder crystals.

¹H-NMR (DMSO-d₆) δ: 3.40 (3H, s), 4.04 (2H, s), 5.23 (2H, s), 6.90 (1H,s), 7.12-7.21 (1H, m), 7.23-7.35 (3H, s), 7.43-7.49 (1H, m), 7.52-7.60(1H, m), 7.78-7.87 (4H, m), 8.19 (1H, d, J=1.8 Hz), 8.33 (1H, s), 9.07(1H, s), 9.97 (1H, s), 11.45 (1H, s).

Example 87

Production of(2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]prop-2-en-1-ol(i) Production of(2E)-5-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrimidin-4-yl]pent-2-en-4-yn-1-ol

The title compound (188.2 mg) was obtained as a brown solid by thereaction in the same manner as in Example 81 (ii) usingN4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodopyrimidine-4,5-diamine(300 mg), 2-penten-4-yn-1-ol (58 mg),bis(triphenylphosphine)palladium(II) dichloride (22.5 mg), copper(I)iodide (7.3 mg), acetonitrile (6.0 mL) and triethylamine (4.5 mL).

¹H-NMR (DMSO-d₆) δ: 4.06-4.15 (2H, m), 5.06 (1H, t, J=5.4 Hz), 5.21 (2H,s), 5.45 (2H, br s), 5.98-6.07 (1H, m), 6.46-6.57 (1H, m), 7.12-7.34(4H, m), 7.39-7.59 (2H, m), 7.92-7.99 (2H, m), 8.55 (1H, br s).

(ii) Production of(2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]prop-2-en-1-ol

The title compound (98 mg) was obtained as pale-yellow powder crystalsby the reaction in the same manner as in Example 81 (iii) using(2E)-5-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrimidin-4-yl]pent-2-en-4-yn-1-ol(170 mg), copper(I) iodide (7.6 mg) and N,N-dimethylformamide (1.5 mL).

¹H-NMR (DMSO-d₆) δ: 4.16-4.24 (2H, m), 5.02-5.09 (1H, m), 5.22 (2H, s),6.40-6.52 (2H, m), 6.66 (1H, d, J=15.9 Hz), 7.13-7.34 (4H, m), 7.41-7.50(1H, m), 7.52-7.60 (1H, m), 8.17 (1H, d, J=2.7 Hz), 8.29 (1H, s), 9.13(1H, br s), 11.38 (1H, br s).

Example 88

Production of3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]propan-1-ol(i) Production of5-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrimidin-4-yl]pent-4-yn-1-ol

To a solution ofN4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodopyrimidine-4,5-diamine(300 mg) and 4-pentyn-1-ol (65 mg) in acetonitrile-triethylamine (6.0mL-4.5 mL) were added bis(triphenylphosphine)palladium(II) dichloride(22.5 mg) and copper(I) iodide (7.3 mg) at room temperature, and themixture was stirred at room temperature under an argon atmosphere for 24hrs. 4-Pentyn-1-ol (65 mg), bis(triphenylphosphine)palladium(II)dichloride (22.5 mg) and copper(I) iodide (7.3 mg) were added to thereaction system and the mixture was stirred at 60° C. for 2 hrs. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (basic silica gel, eluent, ethylacetate→methanol:ethyl acetate=1:19) to give the title compound (157.2mg) as a yellow solid.

¹H-NMR (DMSO-d₆) δ: 1.66-1.79 (2H, m), 2.43-2.58 (2H, m), 3.53 (2H, q,J=5.4 Hz), 4.61 (1H, t, J=5.1 Hz), 5.20 (2H, s), 5.31 (2H, s), 7.11-7.21(2H, m), 7.25-7.33 (2H, m), 7.39-7.50

(1H, m), 7.55 (1H, dd, J=9.0, 2.1 Hz), 7.92-7.94 (2H, m), 8.50 (1H, s).

(ii) Production of3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]propan-1-ol

A mixture of5-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrimidin-4-yl]pent-4-yn-1-ol(140 mg) and copper(I) iodide (19 mg) in N,N-dimethylformamide (2.0 mL)was stirred at 80° C. for 5 hrs. After concentration under reducedpressure, and the residue was separated and purified by columnchromatography (basic silica gel, eluent, ethyl acetate→methanol:ethylacetate=15:85) to give the title compound (95.2 mg) as pale-brown powdercrystals.

¹H-NMR (DMSO-d₆) δ: 1.79-1.91 (2H, m), 2.84 (2H, t, J=7.8 Hz), 3.44-3.52(2H, m), 4.62-4.68 (1H, m), 5.22 (2H, s), 6.24 (1H, s), 7.13-7.35 (4H,m), 7.43-7.59 (2H, m), 8.17 (1H, d, J=2.7 Hz), 8.29 (1H, s), 9.01 (1H,br s), 10.94-11.05 (1H, m).

Example 89

Production of4-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]butan-1-ol(i) Production of6-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrimidin-4-yl]hex-5-yn-1-ol

The title compound (242 mg) was obtained as a brown solid by thereaction in the same manner as in Example 81 (ii) usingN4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodopyrimidine-4,5-diamine(300 mg), 5-hexyn-1-ol (94.2 mg), bis(triphenylphosphine)palladium(II)dichloride (22.5 mg), copper(I) iodide (7.3 mg), acetonitrile (6.0 mL)and triethylamine (4.5 mL).

¹H-NMR (DMSO-d₆) δ: 1.51-1.69 (4H, m), 2.39-2.58 (2H, m), 3.41-3.47 (2H,m), 4.46 (1H, t, J=4.8 Hz), 5.20 (2H, s), 5.28 (2H, br s), 7.12-7.22(2H, m), 7.25-7.33 (2H, m), 7.41-7.49 (1H, m), 7.55 (1H, dd, J=8.6, 2.9Hz), 7.89-7.96 (2H, m), 8.50 (1H, s).

(ii) Production of4-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]butan-1-ol

The title compound (109 mg) was obtained as pale-brown powder crystalsby the reaction in the same manner as in Example 81 (iii) using6-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrimidin-4-yl]hex-5-yn-1-ol(220 mg), copper(I) iodide (9.5 mg) and N,N-dimethylformamide (4.0 mL).

¹H-NMR (DMSO-d₆) δ: 1.44-1.56 (2H, m), 1.67-1.81 (2H, m), 2.80 (2H, t,J=7.8 Hz), 3.45 (2H, t, J=6.0 Hz), 4.40-4.50 (1H, m), 5.21 (2H, s), 6.22(1H, s), 7.12-7.32 (4H, m), 7.42-7.55 (2H, m), 8.15 (1H, d, J=2.7 Hz),8.27 (1H, s), 8.98 (1H, s), 10.93 (1H, br s).

Example 90

Production of6-[(1E)-3-aminoprop-1-enyl]-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production of tert-butyl(2E)-5-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrimidin-4-yl]pent-2-en-4-ynylcarbamate

The title compound (373.8 mg) was obtained as a yellow solid by thereaction in the same manner as in Example 81 (ii) usingN4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodopyrimidine-4,5-diamine(600 mg), tert-butyl pent-2-en-4-ynylcarbamate (0.26 g),bis(triphenylphosphine)palladium(II) dichloride (44.6 mg), copper(I)iodide (14.5 mg), acetonitrile (12 mL) and triethylamine (9 mL).

¹H-NMR (DMSO-d₆) δ: 1.40 (9H, s), 3.66-3.75 (2H, m), 5.21 (2H, s), 5.49(2H, br s), 5.91 (1H, d, J=10.2 Hz), 6.30-6.42 (1H, m), 7.12-7.25 (3H,m), 7.27-7.36 (2H, m), 7.42-7.51 (1H, m), 7.54-7.62 (1H, m), 7.93-7.99(2H, m), 8.58 (1H, s).

(ii) Production of tert-butyl(2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]prop-2-enylcarbamate

The title compound (189 mg) was obtained as pale-brown powder crystalsby the reaction in the same manner as in Example 81 (iii) usingtert-butyl(2E)-5-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrimidin-4-yl]pent-2-en-4-ynylcarbamate(350 mg), copper(I) iodide (12.7 mg) and N,N-dimethylformamide (2.0 mL).

¹H-NMR (DMSO-d₆) δ: 1.41 (9H, s), 3.73-3.85 (2H, m), 5.23 (2H, s),6.22-6.36 (1H, m), 6.48-6.62 (2H, m), 7.14-7.38 (5H, m), 7.42-7.50 (1H,m), 7.52-7.62 (1H, m), 8.18 (1H, s), 8.30 (1H, s), 9.06 (1H, br s),11.29 (1H, br s).

(iii) Production of6-[(1E)-3-aminoprop-1-enyl]-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a solution of tert-butyl(2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]prop-2-enylcarbamate(150 mg) in tetrahydrofuran (6.0 mL) was added 2N hydrochloric acid (3.0mL) at room temperature and the mixture was stirred at 60° C. for 2 hrs.1N Aqueous sodium hydroxide solution was added to alkalize the reactionsystem. After extraction with chloroform, the organic layer was driedover sodium sulfate and concentrated under reduced pressure. Theresultant crystals were collected by filtration. The crystals werewashed with diisopropyl ether to give the title compound (104 mg) aspale-brown powder crystals.

¹H-NMR (DMSO-d₆) δ: 3.42 (2H, d, J=4.2 Hz), 5.22 (2H, s), 6.41-6.50 (2H,m), 6.62 (1H, d, J=15.9 Hz), 7.12-7.35 (4H, m), 7.42-7.50 (1H, m),7.57-7.60 (1H, m), 8.18 (1H, d, J=2.1 Hz), 8.28 (1H, s), 9.20 (1H, brs), 11.39 (1H, br s).

Example 91

Production ofN-{(2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]prop-2-enyl}-2-methoxyacetamide

The title compound (23.2 mg) was obtained as pale-brown powder crystalsby the reaction in the same manner as in Example 82 using6-[(1E)-3-aminoprop-1-enyl]-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(30 mg), methoxyacetic acid (14 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (55 mg),1-hydroxybenzotriazole monohydrate (44 mg), triethylamine (0.1 mL) andN,N-dimethylformamide (5 mL).

¹H-NMR (DMSO-d₆) δ: 3.34 (3H, s), 3.87 (2H, s), 3.95 (2H, t, J=5.4 Hz),5.21 (2H, s), 6.35 (1H, dt, J=16.2, 5.7 Hz), 6.47 (1H, s), 6.56 (1H, d,J=16.2 Hz), 7.12-7.32 (4H, m), 7.41-7.50 (1H, m), 7.62 (1H, dd, J=9.0.2.7 Hz), 8.16-8.25 (2H, m), 8.28 (1H, s), 9.37-9.52 (1H, m), 11.67-11.84(1H, m).

Example 92

Production of(2E)-N-{(2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]prop-2-enyl}-4-(dimethylamino)but-2-enamide

The title compound (25.6 mg) was obtained as pale-yellow powder crystalsby the reaction in the same manner as in Example 82 using6-[(1E)-3-aminoprop-1-enyl]-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(40 mg), (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride (31 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (72 mg),1-hydroxybenzotriazole monohydrate (58 mg), triethylamine (0.13 mL) andN,N-dimethylformamide (5 mL).

¹H-NMR (DMSO-d₆) δ: 2.15 (6H, s), 3.00 (2H, d, J=6.3 Hz), 3.97-4.06 (2H,m), 5.23 (2H, s), 6.10 (1H, d, J=15.3 Hz), 6.27-6.40 (1H, m), 6.51 (1H,s), 6.55-6.68 (2H, m), 7.14-7.36 (4H, m), 7.43-7.60 (2H, m), 8.17 (1H,d, J=2.7 Hz), 8.31 (1H, s), 8.41-8.45 (1H, m), 9.01 (1H, s), 11.22 (1H,s).

Example 93

Production of2-{[2-chloro-4-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)phenoxy]methyl}benzonitrile

The title compound (272 mg) was obtained by the reaction in the samemanner as in Example 2 (ii) using 4-chloro-5H-pyrrolo[3,2-d.]pyrimidine(200 mg) and 2-[(4-amino-2-chlorophenoxy)methyl]benzonitrile (337 mg).

¹H-NMR (DMSO-d₆) δ 5.33 (2H, s), 6.49 (1H, s), 7.32 (1H, d, J=9.0 Hz),7.57-7.68 (3H, m), 7.78-7.80 (2H, m), 7.94 (1H, d, J=8.1 Hz), 8.20 (1H,m), 8.36 (1H, s), 9.32 (1H, br s), 11.1 (1H, br s).

Example 94

Production of3-[2-methyl-4-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)phenoxy]benzonitrile

The title compound (338 mg) was obtained by the reaction in the samemanner as in Example 2 (ii) using 4-chloro-5H-pyrrolo[3,2-d]pyrimidine(200 mg) and 3-(4-amino-2-methylphenoxy)benzonitrile (292 mg).

¹H-NMR (DMSO-d₆) δ 2.16 (3H, s), 6.49 (1H, s), 7.06 (1H, d, J=9.3 Hz),7.21 (1H, m), 7.35 (1H, s), 7.51-7.59 (2H, m), 7.69 (1H, m), 7.80-7.83(2H, m), 8.35 (1H, s), 9.26 (1H, s), 11.1 (1H, br s).

Example 95

Production of3-[2-chloro-4-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)phenoxy]benzonitrile

The title compound (230 mg) was obtained by the reaction in the samemanner as in Example 2 (ii) using 4-chloro-5H-pyrrolo[3,2-d]pyrimidine(150 mg) and 3-(4-amino-2-chlorophenoxy)benzonitrile (219 mg).

¹H-NMR (DMSO-d₆) δ 6.53 (1H, s), 7.26 (1H, m), 7.32 (1H, d, J=8.7 Hz),7.45 (1H, s), 7.58 (2H, d, J=5.7 Hz), 7.70-7.73 (2H, m), 8.41 (2H, s),9.50 (1H, s), 11.1 (1H, br s).

Example 96

Production of2-{[2-methyl-4-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)phenoxy]methyl}benzonitrile

The title compound (250 mg) was obtained by the reaction in the samemanner as in Example 2 (ii) using 4-chloro-5H-pyrrolo[3,2-d]pyrimidine(200 mg) and 2-[(4-amino-2-methylphenoxy)methyl]benzonitrile (310 mg).

¹H-NMR (DMSO-d₆) δ 2.24 (3H, s), 5.26 (2H, s), 6.46 (1H, t, J=1.5 Hz),7.08 (1H, d, J=9.0 Hz), 7.58-7.68 (4H, m), 7.78 (2H, d, J=4.2 Hz), 7.94(1H, d, J=7.5 Hz), 8.29 (1H, s), 9.02 (1H, br s), 11.1 (1H, br s).

Example 97

Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-1H-pyrazolo[4,3-d]pyrimidin-7-amine

A mixture of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (known compoundfrom literature: J. Am. Chem. Soc., 1956, 78, 2418) (150 mg),3-chloro-4-[(3-fluorobenzyl)oxy]aniline (227 mg) and pyridinehydrochloride (156 mg) in 1-methyl-2-pyrrolidone (3 mL) was stirred at120° C. for 10 hrs. After the completion of the reaction, the mixturewas diluted with ethyl acetate and washed with saturated aqueous sodiumhydrogen carbonate and saturated brine. The organic layer wasconcentrated under reduced pressure, and the residue was subjected tosilica gel column chromatography (hexane/ethyl acetate=1/3→1/10) to givethe title compound (220 mg, yield 61%) as a pale-yellow solid.

¹H-NMR (CDCl₃) δ 5.15 (2H, s), 6.96 (1H, d, J=8.7 Hz), 7.03 (1H, m),7.20-7.26 (2H, m), 7.36 (1H, dt, J=5.7, 8.4 Hz), 7.71 (1H, dd, J=2.7,9.0 Hz), 7.81 (1H, d, J=2.7 Hz), 8.14 (1H, s), 8.57 (1H, s).

Example 98

Production ofN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[4,3-d]pyrimidin-7-amine

The title compound (195 mg) was obtained as a brown solid by thereaction in the same manner as in Example 97 using7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (150 mg),3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (193 mg) and pyridinehydrochloride (156 mg).

¹H-NMR (CDCl₃) δ 2.13 (3H, s), 6.89 (1H, d, J=8.4 Hz), 7.11 (1H, d,J=8.1 Hz), 7.15 (1H, dd, J=2.7, 8.4 Hz), 7.50 (1H, dd, J=2.7, 9.0 Hz),7.68 (1H, d, J=2.7 Hz), 8.14 (1H, s), 8.25 (1H, d, J=2.7 Hz), 8.58 (1H,s).

Example 99

Production of methyl4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]methyl}benzoate

The title compound (45 mg) was obtained as a brown solid by the reactionin the same manner as in Example 97 using methyl4-{[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]methyl}benzoate (120mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (87 mg) and pyridinehydrochloride (60 mg).

¹H-NMR (CDCl₃) δ 3.94 (3H, s), 5.11 (2H, s), 5.90 (2H, s), 6.34 (1H, brs), 6.85 (1H, d, J=8.7 Hz), 6.94 (1H, dd, J=2.7, 8.7 Hz), 7.01 (1H, m),7.16-7.22 (2H, m), 7.32 (2H, d, J=8.7 Hz), 7.35 (1H, m), 8.14 (2H, d,J=8.7 Hz), 8.18 (1H, s), 8.51 (1H, s).

Example 100

Production of methyl4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoate

The title compound (140 mg) was obtained as a pale-yellow solid by thereaction in the same manner as in Example 97 using methyl4-{[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoate (150mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (109 mg) and pyridinehydrochloride (75 mg).

¹H-NMR (CDCl₃) δ 3.92 (3H, s), 5.16 (2H, s), 5.62 (2H, s), 6.97 (1H, d,J=8.8 Hz), 7.02 (1H, m), 7.18-7.42 (4H, m), 7.55-7.68 (2H, m), 8.00-8.08(4H, m), 8.50 (1H, s).

Example 101

Production of4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]methyl}benzoicacid

To a solution of methyl4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]methyl}benzoate(25 mg) in a mixed solvent of tetrahydrofuran/methanol (1:1, 1 mL) wasadded 1N aqueous sodium hydroxide solution (0.5 mL), and the mixture wasstirred at room temperature for 1 hr. After the completion of thereaction, 1N aqueous hydrochloric acid solution (0.5 mL) and water (1mL) were added under ice-cooling, and the mixture was stirred at roomtemperature for 1 hr. The resultant solid was collected by filtration,and washed with diisopropyl ether and dried to give the title compound(16 mg) as pale-yellow crystals.

¹H-NMR (DMSO-d₆) δ 5.24 (2H, s), 6.10 (2H, s), 7.13-7.31 (5H, m),7.42-7.47 (2H, m), 7.70 (1H, m), 7.83-7.91 (2H, m), 8.27 (1H, s), 8.35(1H, s), 8.81 (1H, s), 12.9 (1H, br s).

Example 102

Production of4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoicacid

The title compound (130 mg) was obtained as pale-yellow crystals by thereaction in the same manner as in Example 101 using methyl4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoate(150 mg) and 1N aqueous sodium hydroxide solution (6 mL).

¹H-NMR (DMSO-d₆) δ 5.26 (2H, s), 5.85 (2H, s), 7.15-7.32 (4H, m), 7.41(2H, d, J=8.1 Hz), 7.45 (1H, m), 7.72 (1H, dd, J=2.4, 8.7 Hz), 7.94 (2H,d, J=8.1 Hz), 8.06 (1H, d, J=2.1 Hz), 8.65 (1H, s), 8.85 (1H, s), 11.4(1H, br s).

Example 103

Production of 4-{[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]methyl}benzoic acid

Methyl 4-{[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]methyl}benzoate wasobtained as a mixture with 1-methyl-2-pyrrolidone by the reaction in thesame manner as in Example 97 using methyl4-{[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]methyl}benzoate (120mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (87 mg) and pyridinehydrochloride (60 mg).

The title compound (20 mg) was obtained as yellow crystals by thereaction in the same manner as in Example 101 using the above-mentionedmixture and 1N aqueous sodium hydroxide solution (1 mL).

¹H-NMR (DMSO-d₆) δ 2.17 (3H, s), 2.43 (3H, s), 6.12 (2H, s), 6.91 (2H,d, J=8.7 Hz), 7.12-7.24 (4H, m), 7.38-7.47 (2H, m), 7.85 (2H, d, J=8.1Hz), 8.16 (1H, d, J=2.4 Hz), 8.28 (1H, s), 8.35 (1H, s), 8.81 (1H, s).

Example 104

Production of methyl4-{[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoate

The title compound (160 mg) was obtained as pale-yellow crystals by thereaction in the same manner as in Example 97 using methyl4-{[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoate (150mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (93 mg) and pyridinehydrochloride (75 mg).

¹H-NMR (CDCl₃) δ 2.27 (3H, s), 2.52 (3H, s), 3.91 (3H, s), 5.60 (2H, s),6.90 (1H, d, J=8.7 Hz), 7.08-7.09 (2H, m), 7.31 (1H, s), 7.66 (1H, dd,J=3.0, 9.0 Hz), 7.76 (1H, d, J=2.4 Hz), 7.86 (1H, m), 8.02 (2H, s), 8.04(1H, s), 8.25 (1H, m), 8.51 (1H, s).

Example 105

Production of4-{[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoicacid

The title compound (120 mg) was obtained as white crystals by thereaction in the same manner as in Example 101 using methyl4-{[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoate(150 mg) and 1N aqueous sodium hydroxide solution (3 mL).

¹H-NMR (DMSO-d₆) δ 2.17 (3H, s), 2.43 (3H, s), 5.80 (2H, s), 6.93 (1H,d, J=8.7 Hz), 7.13-7.23 (2H, m), 7.37 (2H, d, J=7.8 Hz), 7.84 (1H, dd,J=2.1, 9.0 Hz), 7.92-7.97 (2H, m), 8.15 (1H, d, J=2.1 Hz), 8.32 (1H, s),8.67 (1H, s), 10.09 (1H, s), 13.0 (1H, br s).

Example 106

Production of4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}-N-(2-methoxyethyl)benzamide

A solution of4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoicacid (45 mg), 2-methoxyethylamine (9 mg), 1-hydroxybenzotriazole (18mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (26mg) and triethylamine (0.08 mL) in N,N-dimethylformamide (2 mL) wasstirred at room temperature for 30 hrs. After the completion of thereaction, the reaction solution was concentrated under reduced pressure,and the residue was subjected to silica gel column chromatography (basicsilica gel; ethyl acetate) to give the title compound (115 mg) as apale-yellow solid.

¹H-NMR (CDCl₃) δ 3.38 (3H, s), 3.54-3.57 (2H, m), 3.63-3.68 (2H, m),5.12 (2H, s), 5.60 (2H, s), 6.53 (1H, br s), 6.97 (1H, d, J=8.7 Hz),7.02 (1H, m), 7.20-7.40 (3H, m), 7.31 (1H, d, J=8.4 Hz), 7.64 (1H, d,J=8.7 Hz), 7.65 (1H, d, J=8.4 Hz), 7.79 (1H, d, J=8.4 Hz), 8.00-8.01(2H, m), 8.50 (1H, s).

Example 107

Production ofN-(2-methoxyethyl)-4-{[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzamide

The title compound (30 mg) was obtained as white crystals by thereaction in the same manner as in Example 106 using4-{[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoicacid (45 mg), 2-methoxyethylamine (10 mg), 1-hydroxybenzotriazole (20mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (28mg) and triethylamine (0.08 mL).

¹H-NMR (CDCl₃) δ 2.29 (3H, s), 2.53 (3H, s), 3.38 (3H, s), 3.54-3.57(2H, m), 3.63-3.68 (2H, m), 5.62 (2H, s), 6.51 (1H, br s), 6.93 (1H, d,J=8.7 Hz), 7.09-7.10 (2H, m), 7.34 (2H, d, J=8.1 Hz), 7.62-7.69 (2H, m),7.76 (1H, m), 7.80 (1H, d, J=8.1 Hz), 8.02 (1H, s), 8.26 (1H, m), 8.51(1H, s).

Example 108

Production of N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2-(4-nitrophenyl)-2H-pyrazolo[4, 3-0]pyrimidin-7-amine (i)Production of7-(methylthio)-2-(4-nitrophenyl)-2H-pyrazolo[4,3-d]pyrimidine

To a solution of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (500 mg) inN,N-dimethylformamide (10 mL) was added potassium tert-butoxide (405 mg)under ice-cooling, and the mixture was stirred at room temperature for10 min. Subsequently, 1-fluoro-4-nitrobenzene (465 mg) was added, andthe mixture was stirred at 70° C. for 30 min. After the completion ofthe reaction, water was added to the reaction mixture and the mixturewas stirred at room temperature for 30 min. The resultant solid wascollected by filtration, washed with diisopropyl ether and dried to givethe title compound (860 mg) as brown crystals.

¹H-NMR (DMSO-d₆) δ 2.72 (3H, s), 8.39 (2H, d, J=8.7 Hz), 8.46 (2H, d,J=8.7 Hz), 8.76 (1H, s), 9.64 (1H, s).

(ii) Production ofN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2-(4-nitrophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine

The title compound (667 mg) was obtained as a pale-yellow solid by thereaction in the same manner as in Example 97 using7-(methylthio)-2-(4-nitrophenyl)-2H-pyrazolo[4,3-d]pyrimidine (430 mg),3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (321 mg) and pyridinehydrochloride (259 mg).

¹H-NMR (CDCl₃) δ 2.32 (3H, s), 2.54 (3H, s), 6.95 (1H, d, J=9.0 Hz),7.07-7.15 (2H, m), 7.71 (1H, dd, J=2.7, 8.4 Hz), 7.80-7.81 (2H, m), 8.12(2H, d, J=9.3 Hz), 8.25 (1H, dd, J=0.6, 2.7 Hz), 8.45 (2H, d, J=9.3 Hz),8.55 (1H, s), 8.57 (1H, s).

Example 109

Production of2-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2H-pyrazolo[4,3-d]pyrimidin-7-amine

To a solution ofN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2-(4-nitrophenyl)-2H-pyrazolo[4,3-0]pyrimidin-7-amine (200 mg) in a mixed solvent of ethanol/water (9:1,6 mL) was added calcium chloride (90%, 28 mg) and the mixture wasstirred at 100° C. for 10 min. Reduced iron (90%, 164 mg) was added atroom temperature, and the mixture was stirred at 100° C. for 5 hrs.After the completion of the reaction, the reaction mixture was filtered(celite), and the filtrate was concentrated under reduced pressure.Water was added to the residue and the mixture was diluted with ethylacetate and washed with water and saturated brine. The organic layer wasdried over anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/methylene chloride=10/1) to give the titlecompound (140 mg) as a white solid.

¹H-NMR (DMSO-d₆) δ 2.20 (3H, s), 2.44 (3H, s), 5.55 (2H, s), 6.71-6.74(2H, m), 6.95-6.98 (1H, m), 7.18-7.23 (2H, m), 7.73-7.76 (2H, m), 7.901(1H, m), 8.03 (1H, br s), 8.18 (1H, br s), 8.34 (1H, br s), 8.94 (1H, brs), 10.05 (1H, br s).

Example 110

Production of2-methoxy-N-{4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]phenyl}acetamide

The title compound (64 mg) was obtained as white crystals by thereaction in the same manner as in Example 106 using2-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2H-pyrazolo[4,3-d]pyrimidin-7-amine(100 mg), methoxyacetic acid (30 mg), 1-hydroxybenzotriazole (48 mg),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (68 mg)and triethylamine (0.20 mL).

¹H-NMR (CDCl₃) δ 2.26 (3H, s), 2.53 (3H, s), 3.55 (3H, s), 4.07 (2H, s),6.92 (1H, d, J=8.7 Hz), 7.12-7.25 (2H, m), 7.35-7.45 (3H, m), 7.70-7.83(4H, m), 8.19 (1H, d, J=2.4 Hz), 8.44 (2H, s), 8.50 (1H, s).

Example 111

Production of2-(N,N-dimethylamino)-N-{4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]phenyl}acetamide

The title compound (60 mg) was obtained as white crystals by thereaction in the same manner as in Example 106 using2-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2H-pyrazolo[4,3-d]pyrimidin-7-amine(100 mg), N,N-dimethylglycine hydrochloride (46 mg),1-hydroxybenzotriazole (48 mg),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (68 mg)and triethylamine (0.20 mL).

¹H-NMR (CDCl₃) δ 2.31 (3H, s), 2.43 (6H, s), 2.53 (3H, s), 3.14 (2H, s),6.95 (1H, d, J=9.0 Hz), 7.09-7.11 (2H, m), 7.70-7.76 (2H, m), 7.81-7.85(5H, m), 8.27 (1H, m), 8.43 (1H, s), 8.55 (1H, s), 9.35 (1H, br s).

Example 112

Production of methyl4-({4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]phenyl}amino)-4-oxobutanoate

The title compound (175 mg) was obtained as white crystals by thereaction in the same manner as in Example 106 using2-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2H-pyrazolo[4,3-d]pyrimidin-7-amine(150 mg), succinic acid monomethyl ester (66 mg), 1-hydroxybenzotriazole(72 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(102 mg) and triethylamine (0.30 mL).

¹H-NMR (CDCl₃) δ 2.30 (3H, s), 2.53 (3H, s), 2.73-2.75 (2H, m),2.79-2.81 (2H, m), 3.75 (3H, s), 6.94 (1H, d, J=8.7 Hz), 7.10-7.12 (2H,m), 7.69-7.74 (3H, m), 7.79-7.82 (4H, m), 8.08 (1H, br s), 8.27 (1H, dd,J=0.6, 2.4 Hz), 8.42 (1H, s), 8.53 (1H, s).

Example 113

Production of4-({4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]phenyl)amino)-4-oxobutanoic}acid

The title compound (98 mg) was obtained as white crystals by thereaction in the same manner as in Example 101 using methyl4-({4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]phenyl}amino)-4-oxobutanoate(175 mg) and 1N aqueous sodium hydroxide solution (0.5 mL).

¹H-NMR (DMSO-d₆) δ 2.21 (3H, s), 2.44 (3H, s), 2.50-2.61 (4H, m), 6.97(1H, d, J=8.4 Hz), 7.20-7.22 (2H, m), 7.81-7.93 (4H, m), 8.03-8.09 (3H,m), 8.18 (1H, m), 8.36 (1H, s), 9.13 (1H, s), 10.2 (1H, br s), 10.3 (1H,s).

Example 114

Production of2-(2-methoxyethoxy)-N-{4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]phenyl}acetamide

The title compound (88 mg) was obtained as white crystals by thereaction in the same manner as in Example 106 using2-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2H-pyrazolo[4,3-d]pyrimidin-7-amine(130 mg), (2-methoxyethoxy)acetic acid (58 mg), 1-hydroxybenzotriazole(62 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(88 mg) and triethylamine (0.26 mL).

¹H-NMR (CDCl₃) δ 2.30 (3H, s), 2.53 (3H, s), 3.52 (3H, s), 3.63-3.66(2H, m), 3.80-3.82 (2H, m), 4.16 (2H, s), 6.94 (1H, d, J=8.7 Hz),7.07-7.10 (2H, m), 7.71 (1H, d, J=8.7 Hz), 7.80 (1H, m), 7.83 (4H, s),8.27 (1H, s), 8.43 (1H, s), 8.54 (1H, s), 9.16 (1H, s).

Example 115

Production of methyl4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]benzoate(i) Production of methyl4-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]benzoate

To a solution of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (100 mg)and methyl 4-fluorobenzoate (102 mg) in 1-methyl-2-pyrrolidone (2 mL)was added potassium carbonate (125 mg), and the mixture was stirred at120° C. for 3 hrs. After the completion of the reaction, water was addedto the reaction mixture and the mixture was stirred at room temperaturefor 30 min. The resultant solid was collected by filtration, washed withdiisopropyl ether and dried to give the title compound (90 mg) as yellowcrystals.

¹H-NMR (CDCl₃) δ 2.76 (3H, s), 3.98 (3H, s), 8.04 (2H, d, J=8.4 Hz),8.24 (2H, d, J=8.4 Hz), 8.63 (1H, s), 8.77 (1H, s).

(ii) Production of methyl4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]benzoate

The title compound (135 mg) was obtained as a pale-yellow solid by thereaction in the same manner as in Example 97 using methyl4-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]benzoate (115 mg),3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (82 mg) and pyridinehydrochloride (66 mg).

¹H-NMR (CDCl₃) δ 2.32 (3H, s), 2.54 (3H, s), 3.99 (3H, s), 6.95 (1H, d,J=8.7 Hz), 7.10-7.12 (2H, m), 7.73 (1H, dd, J=2.7, 8.7 Hz), 7.81-7.82(2H, m), 8.00 (2H, d, J=8.4 Hz), 8.26 (2H, d, J=8.4 Hz), 8.27 (1H, s),8.55 (1H, s), 8.56 (1H, s).

Example 116

Production of4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]benzoicacid

The title compound (91 mg) was obtained as white crystals by thereaction in the same manner as in Example 101 using methyl4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]benzoate(110 mg) and 1N aqueous sodium hydroxide solution (0.4 mL).

¹H-NMR (DMSO-d₆) δ 2.21 (3H, s), 2.44 (3H, s), 6.98 (1H, d, J=9.0 Hz),7.21-7.26 (2H, m), 7.90 (1H, dd, J=2.7, 8.7 Hz), 8.03 (1H, m), 8.12-8.22(6H, m), 8.38 (1H, s), 9.30 (1H, s), 10.3 (1H, br s).

Example 117

Production ofN-(2-methoxyethyl)-4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]benzamide

The title compound (63 mg) was obtained as white crystals by thereaction in the same manner as in Example 106 using4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]benzoicacid (75 mg), 2-methoxyethylamine (17 mg), 1-hydroxybenzotriazole (34mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (48mg) and triethylamine (0.14 mL).

¹H-NMR (CDCl₃) δ 2.31 (3H, s), 2.54 (3H, s), 3.43 (3H, s), 3.60-3.63(2H, m), 3.69-3.74 (2H, m), 6.61 (1H, br s), 6.96 (1H, d, J=8.7 Hz),7.10-7.12 (2H, m), 7.72 (1H, dd, J=2.4, 8.4 Hz), 7.81 (1H, t, J=3.3 Hz),8.00 (4H, s), 8.27 (1H, m), 8.53 (1H, s), 8.55 (1H, s).

Example 118

Production of{4-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]phenyl}methanol(i) Production of4-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]benzaldehyde

The title compound (60 mg) was obtained as pale-yellow crystals by thereaction in the same manner as in Example 115 (i) usingN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-1H-pyrazolo[4,3-d]pyrimidin-7-amine(100 mg) and 4-fluorobenzaldehyde (37 mg).

¹H-NMR (DMSO-d₆) δ 5.26 (2H, s), 7.16-7.35 (4H, m), 7.46 (1H, m), 7.93(1H, dd, J=2.6, 8.8 Hz), 8.18 (2H, d, J=8.4 Hz), 8.30 (1H, d, J=2.2 Hz),8.38-8.43 (3H, m), 9.40 (1H, s), 10.1 (1H, s), 10.3 (1H, s).

(ii) Production of{4-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]phenyl}methanol

To a solution of4-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]benzaldehyde(50 mg) in methanol (2 mL) was added sodium borohydride (2 mg) underice-cooling, and the mixture was stirred for 30 min. After thecompletion of the reaction, the reaction solution was concentrated underreduced pressure, and the residue was subjected to silica gel columnchromatography (tetrahydrofuran/ethyl acetate=1/1) to give the titlecompound (20 mg) as a white solid.

¹H-NMR (DMSO-d₆) δ 4.60 (2H, d, J=5.8 Hz), 5.25 (2H, s), 5.38 (1H, t,J=5.8 Hz), 7.16-7.35 (3H, m), 7.49 (1H, m), 7.56 (2H, d, J=8.8 Hz), 7.93(1H, m), 8.09 (2H, d, J=8.8 Hz), 8.30 (1H, d, J=2.4 Hz), 8.38 (1H, s),9.22 (1H, s), 10.2 (1H, s).

Example 119

Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-[4-({[2-(methylsulfonyl)ethyl]amino}methyl)phenyl]-2H-pyrazolo[4,3-d]pyrimidin-7-amine

To a solution of4-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]benzaldehyde(80 mg) and 2-(methylsulfonyl)ethylamine hydrochloride (40 mg) inN,N-dimethylformamide (2 mL) was added acetic acid (0.02 mL), and themixture was stirred at room temperature for 1 hr. Subsequently, sodiumtriacetoxyborohydride (54 mg) was added, and the mixture was stirred atthe same temperature for 2 hrs. After the completion of the reaction,saturated aqueous sodium hydrogen carbonate was added, and the mixturewas concentrated under reduced pressure. The residue was extracted withethyl acetate, and the organic layer was washed with water and saturatedbrine and concentrated under reduced pressure. The residue was subjectedto silica gel column chromatography (ethyl acetate/methanol=5/1) to givethe title compound (70 mg) as a white solid.

¹H-NMR (CDCl₃) δ 3.02 (3H, s), 3.22 (4H, s), 3.92 (2H, s), 5.17 (2H, s),6.98-7.04 (2H, m), 7.21-7.26 (3H, m), 7.36 (1H, m), 7.52 (2H, d, J=8.1Hz), 7.68-7.71 (2H, m), 7.84 (2H, d, J=8.1 Hz), 8.05 (1H, d, J=2.4 Hz),8.45 (1H, s), 8.54 (1H, s).

Example 120

Production of2-({4-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]benzyl}amino)ethanol

The title compound (83 mg) was obtained as pale-yellow crystals by thereaction in the same manner as in Example 119 using4-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]benzaldehyde(120 mg), ethanolamine (23 mg) and sodium triacetoxyborohydride (134mg).

¹H-NMR (DMSO-d₆) δ 2.59 (2H, t, J=6.0 Hz), 3.48 (2H, m), 3.80 (2H, s),4.51 (1H, br s), 5.25 (2H, s), 7.16-7.34 (5H, m), 7.46 (1H, m), 7.57(2H, d, J=7.8 Hz), 7.91 (1H, dd, J=1.8, 9.0 Hz), 8.07 (2H, d, J=7.8 Hz),8.30 (1H, d, J=1.8 Hz), 8.38 (1H, s), 9.21 (1H, s), 10.2 (1H, s).

Example 121

Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-(4-{[(2-morpholin-4-ylethyl)amino]methyl}phenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine

The title compound (68 mg) was obtained as pale-yellow crystals by thereaction in the same manner as in Example 119 using4-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]benzaldehyde(80 mg), N-(2-aminoethyl)morpholine (33 mg) and sodiumtriacetoxyborohydride (54 mg).

¹H-NMR (CDCl₃) δ 2.44 (4H, t, J=4.5 Hz), 2.53 (2H, t, J=6.0 Hz), 2.74(2H, t, J=6.0 Hz), 3.70 (4H, t, J=4.5 Hz), 3.91 (2H, s), 5.16 (2H, s),6.98 (1H, d, J=8.7 Hz), 7.02 (1H, m), 7.19-7.25 (3H, m), 7.35 (1H, m),7.52 (2H, d, J=8.7 Hz), 7.67-7.71 (2H, m), 7.82 (2H, d, J=8.7 Hz), 8.04(1H, d, J=2.4 Hz), 8.43 (1H, s), 8.52 (1H, s).

Example 122

Production of2-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethanol

2-[7-({3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethylbenzoate was obtained as a mixture with 1-methyl-2-pyrrolidone by thereaction in the same manner as in Example 97 using2-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethyl benzoate (130mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (104 mg) and pyridinehydrochloride (72 mg).

The title compound (60 mg) was obtained as a pale-yellow solid by thereaction in the same manner as in Example 101 using the above-mentionedmixture and 1N aqueous sodium hydroxide solution (0.2 mL).

¹H-NMR (DMSO-d₆) δ 3.87-3.93 (2H, m), 4.75 (2H, t, J=5.7 Hz), 5.24 (2H,s), 6.27 (1H, t, J=3.9 Hz), 7.13-7.32 (4H, m), 7.48 (1H, m), 7.55 (1H,dd, J=2.4, 9.3 Hz), 7.86 (1H, d, J=1.8 Hz), 8.17 (1H, s), 8.36 (1H, s),9.85 (1H, s).

Example 123

Production of2-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]ethanol

2-[7-({3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]ethylbenzoate was obtained as a mixture with 1-methyl-2-pyrrolidone by thereaction in the same manner as in Example 97 using2-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]ethyl benzoate (120mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (96 mg) and pyridinehydrochloride (66 mg).

The title compound (86 mg) was obtained as a pale-yellow solid by thereaction in the same manner as in Example 101 using the above-mentionedmixture and 1N aqueous sodium hydroxide solution (0.2 mL).

¹H-NMR (DMSO-d₆) δ 3.88-3.93 (2H, m), 4.50 (2H, t, J=5.4 Hz), 5.04 (1H,t, J=5.7 Hz), 5.23 (2H, s), 7.14-7.32 (4H, m), 7.46 (1H, m), 7.88 (1H,dd, J=2.7, 9.0 Hz), 8.28 (1H, d, J=1.8 Hz), 8.31 (1H, s), 8.45 (1H, s),10.12 (1H, s).

Example 124

Production of2-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethanol

2-[7-({3-Methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethyl benzoate wasobtained as a mixture with 1-methyl-2-pyrrolidone by the reaction in thesame manner as in Example 101 using2-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethyl benzoate (190mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (129 mg) and pyridinehydrochloride (105 mg).

The title compound (88 mg) was obtained as a pale-yellow solid by thereaction in the same manner as in Example 101 using the above-mentionedmixture and 1N aqueous sodium hydroxide solution (0.3 mL).

¹H-NMR (CDCl₃) δ 2.22 (3H, s), 2.48 (3H, s), 4.25 (2H, br s), 4.76 (2H,br s), 6.01 (1H, br s), 6.86 (1H, d, J=8.7 Hz), 7.08 (1H, d, J=8.7 Hz),7.16 (1H, dd, J=3.0, 8.7 Hz), 7.45 (1H, dd, J=2.7, 8.7 Hz), 7.56 (1H, d,J=2.7 Hz), 8.05 (1H, d, J=3.0 Hz), 8.37 (1H, s), 9.88 (1H, s).

Example 125

Production of2-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]ethanol

2-[7-({3-Methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]ethylbenzoate was obtained as a mixture with 1-methyl-2-pyrrolidone by thereaction in the same manner as in Example 97 using2-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]ethyl benzoate (115mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (78 mg) and pyridinehydrochloride (63 mg).

The title compound (95 mg) was obtained as a pale-yellow solid by thereaction in the same manner as in Example 101 using the above-mentionedmixture and 1N aqueous sodium hydroxide solution (0.3 mL).

¹H-NMR (CDCl₃) δ 2.24 (3H, s), 2.52 (3H, s), 4.16 (2H, t, J=4.5 Hz),4.26 (1H, br s), 4.50-4.53 (2H, m), 6.86 (1H, d, J=8.7 Hz), 7.05-7.12(2H, m), 7.57-7.61 (2H, m), 7.69 (1H, d, J=2.7 Hz), 7.97 (1H, s), 8.23(1H, m), 8.34 (1H, s).

Example 126

Production of3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]propanol

The title compound (240 mg) was obtained as a pale-yellow solid by thereaction in the same manner as in Example 122 using3-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]propyl benzoate (623mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (477 mg) and pyridinehydrochloride (329 mg) and 1N aqueous sodium hydroxide solution (0.5mL).

¹H-NMR (DMSO-d₆) δ 1.97-2.04 (2H, m), 3.25-3.28 (2H, m), 4.71 (2H, t,J=6.6 Hz), 5.27 (2H, s), 5.44 (1H, t, J=4.8 Hz), 7.16-7.34 (4H, m), 7.48(1H, m), 7.57 (1H, dd, J=2.7, 9.0 Hz), 7.82 (1H, d, J=2.4 Hz), 8.19 (1H,s), 8.35 (1H, s), 9.22 (1H, s).

Example 127

Production of3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]propanol

The title compound (512 mg) was obtained as a pale-yellow solid by thereaction in the same manner as in Example 123 using3-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]propyl benzoate (556mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (426 mg), pyridinehydrochloride (293 mg) and 1N aqueous sodium hydroxide solution (10 mL).

¹H-NMR (DMSO-d₆) δ 2.06-2.13 (2H, m), 3.41-3.46 (2H, m), 4.53 (2H, t,J=6.9 Hz), 4.70 (1H, t, J=5.4 Hz), 5.24 (2H, s), 7.16-7.33 (4H, m), 7.46(1H, m), 7.89 (1H, dd, J=2.4, 9.0 Hz), 8.28 (1H, d, J=2.4 Hz), 8.32 (1H,s), 8.51 (1H, s), 10.12 (1H, s).

Example 128

Production of4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5,6-dihydro-4H-pyrazolo[4,5,1-de]pteridine

A solution of2-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethanol(40 mg), 1,1′-(azodicarbonyl)dipiperidine (48 mg) and tributylphosphine(40 mg) in tetrahydrofuran (2 mL) was stirred at room temperature for 15hrs. After the completion of the reaction, water was added to thereaction mixture and the mixture was diluted with ethyl acetate andwashed with saturated brine. The organic layer was dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=4/1→1/4) to give the title compound (31 mg) as a white solid.

¹H-NMR (CDCl₃) δ 4.32 (2H, dd, J=5.0, 6.6 Hz), 4.62 (2H, dd, J=5.0, 6.6Hz), 5.19 (2H, s), 7.04 (1H, d, J=9.2 Hz), 7.05 (1H, m), 7.18-7.26 (2H,m), 7.32-7.43 (2H, m), 7.55 (1H, d, J=2.6 Hz), 8.09 (1H, s), 8.51 (1H,s).

Example 129

Production of 4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5,6-dihydro-4H-pyrazolo[4,5,1-de]pteridine

The title compound (21 mg) was obtained as a pale-yellow solid by thereaction in the same manner as in Example 128 using2-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethanol(30 mg), 1,1′-(azodicarbonyl)dipiperidine (40 mg) and tributylphosphine(32 mg).

¹H-NMR (CDCl₃) δ 2.34 (3H, s), 2.55 (3H, s), 4.36 (2H, t, J=5.7 Hz),4.64 (2H, t, J=5.7 Hz), 6.92 (1H, d, J=8.4 Hz), 7.13 (1H, d, J=8.4 Hz),7.20 (1H, dd, J=2.7, 8.4 Hz), 7.27 (1H, dd, J=2.4, 8.4 Hz), 7.41 (1H, d,J=2.4 Hz), 8.09 (1H, s), 8.30 (1H, d, J=2.7 Hz), 8.53 (1H, s).

Example 130

Production of6-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6,7,8,9-tetrahydro-1,3,5,6,9a-pentaazabenzo[cd]-azulene

The title compound (29 mg) was obtained as a pale-yellow solid by thereaction in the same manner as in Example 128 using3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]propanol(60 mg), 1,1′-(azodicarbonyl)dipiperidine (70 mg) and tributylphosphine(57 mg).

¹H-NMR (CDCl₃) δ 2.49-2.56 (2H, m), 4.03 (2H, m), 4.62 (2H, t, J=5.7Hz), 5.19 (2H, s), 7.02 (1H, d, J=8.7 Hz), 7.05 (1H, m), 7.15 (1H, dd,J=2.7, 9.0 Hz), 7.21-7.26 (2H, m), 7.35-7.42 (2H, m), 8.12 (1H, s), 8.37(1H, s).

Example 131

Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-(3-{[2-(methylsulfonyl)ethyl]amino}propyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine

A solution of3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]propanol(50 mg), N-[2-(methylsulfonyl)ethyl]-2-nitrobenzenesulfonamide (47 mg),1,1′-(azodicarbonyl)dipiperidine (59 mg) and tributylphosphine (47 mg)in tetrahydrofuran (2 mL) was stirred at room temperature for 4 hrs.After the completion of the reaction, water was added to the reactionmixture and the mixture was diluted with ethyl acetate and washed withsaturated brine. The organic layer was dried over anhydrous magnesiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethylacetate/methanol=4/1→1/4) to giveN-{3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]propyl}-N-[2-(methylsulfonyl)ethyl]-2-nitrobenzenesulfonamide.To a solution of this compound in tetrahydrofuran (2 mL) were added2-mercaptoethanol (12 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (23mg), and the mixture was stirred at room temperature for 3 hrs. Afterthe completion of the reaction, the reaction mixture was concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (ethyl acetate/methanol=10/1) to give the titlecompound (34 mg) as a white solid.

¹H-NMR (CDCl₃) δ 2.05-2.14 (2H, m), 2.57 (2H, t, J=6.3 Hz), 3.08 (3H,s), 3.14-3.16 (2H, m), 3.22-3.26 (2H, m), 4.54 (2H, t, J=6.3 Hz), 5.16(2H, s), 6.97 (1H, d, J=8.7 Hz), 7.02 (1H, m), 7.20-7.26 (3H, m), 7.36(1H, dt, J=6.3, 7.8 Hz), 7.71 (1H, dd, J=2.7, 9.0 Hz), 7.99 (2H, s),8.09 (1H, d, J=2.7 Hz), 8.49 (1H, s).

Example 132

Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-{3-[(2-morpholin-4-ylethyl)amino]propyl}-2H-pyrazolo[4,3-d]pyrimidin-7-amine

The title compound (32 mg) was obtained as a pale-yellow solid by thereaction in the same manner as in Example 131 using3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]propanol(60 mg), N-(2-morpholin-4-ylethyl)-2-nitrobenzenesulfonamide (53 mg),1,1′-(azodicarbonyl)dipiperidine (71 mg), tributylphosphine (57 mg),2-mercaptoethanol (12 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (23mg).

¹H-NMR (CDCl₃) δ 2.42-2.51 (8H, m), 2.59-2.72 (4H, m), 3.70 (4H, t,J=4.8 Hz), 4.51 (2H, t, J=6.8 Hz), 5.15 (2H, s), 6.97 (1H, d, J=8.8 Hz),7.02 (1H, m), 7.19-7.26 (2H, m), 7.31-7.42 (2H, m), 7.66 (2H, m), 7.98(1H, s), 8.01 (1H, d, J=2.8 Hz), 8.49 (1H, s).

Example 133

Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-{3-[(2-methoxyethyl)amino]propyl}-2H-pyrazolo[4,3-d]pyrimidin-7-amine

The title compound (26 mg) was obtained as a pale-yellow solid by thereaction in the same manner as in Example 131 using3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]propanol(60 mg), N-(2-methoxyethyl)-2-nitrobenzenesulfonamide (44 mg),1,1′-(azodicarbonyl)dipiperidine (71 mg), tributylphosphine (57 mg),2-mercaptoethanol (12 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (23mg).

¹H-NMR (CDCl₃) δ 2.14-2.18 (2H, m), 2.61 (2H, t, J=6.6 Hz), 2.76 (2H, t,J=5.1 Hz), 3.37 (3H, s), 3.50 (2H, t, J=5.1 Hz), 4.52 (2H, t, J=6.6 Hz),5.15 (2H, s), 6.97 (1H, d, J=9.0 Hz), 7.01 (1H, m), 7.18-7.26 (4H, m),7.35 (1H, m), 7.58 (1H, br s), 7.65 (1H, dd, J=2.4, 8.7 Hz), 7.99-8.00(2H, m), 8.48 (1H, s).

Example 134

Production of2-[[2-chloro-4-(1H-pyrazolo[4,3-d]pyrimidin-7-ylamino)phenoxy]methyl]benzonitrile

The title compound (96 mg) was obtained as a pale-yellow solid by thereaction in the same manner as in Example 97 using7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (80 mg),2-[(4-amino-2-chlorophenoxy)methyl]benzonitrile (125 mg) and pyridinehydrochloride (83 mg).

¹H-NMR (DMSO-d₆) δ2.23 (3H, s), 5.26 (2H, s), 7.09 (1H, d, J=8.7 Hz),7.54-7.77 (5H, m), 7.92 (1H, d, J=8.7 Hz), 8.20 (1H, br s), 8.34 (1H, brs), 9.45 (1H, br s), 12.8 (1H, br s).

Example 135

Production of2-{[2-methyl-4-(1H-pyrazolo[4,3-d]pyrimidin-7-ylamino)phenoxy]methyl}benzonitrile

The title compound (110 mg) was obtained as a pale-yellow solid by thereaction in the same manner as in Example 97 using7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (80 mg),2-[(4-amino-2-methylphenoxy)methyl]benzonitrile (115 mg) and pyridinehydrochloride (83 mg).

¹H-NMR (DMSO-d₆) δ 2.23 (3H, s), 5.26 (2H, s), 7.09 (1H, d, J=8.7 Hz),7.54-7.77 (5H, m), 7.92 (1H, d, J=8.7 Hz), 8.20 (1H, br s), 8.34 (1H, brs), 9.45 (1H, br s), 12.8 (1H, br s).

Example 136

Production of3-[2-chloro-4-(1H-pyrazolo[4,3-d]pyrimidin-7-ylamino)phenoxy]benzonitrile

The title compound (89 mg) was obtained as a pale-yellow solid by thereaction in the same manner as in Example 97 using7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (80 mg),3-(4-amino-2-chlorophenoxy)benzonitrile (117 mg) and pyridinehydrochloride (83 mg).

¹H-NMR (DMSO-d₆) δ 7.26-7.35 (2H, m), 7.46 (1H, m), 7.55-7.59 (2H, m),7.89 (1H, m), 8.39 (1H, br s), 8.46 (2H, s), 10.16 (1H, br s), 12.6 (1H,br s).

Example 137

Production of3-[2-methyl-4-(1H-pyrazolo[4,3-d]pyrimidin-7-ylamino)phenoxy]benzonitrile

The title compound (98 mg) was obtained as a pale-yellow solid by thereaction in the same manner as in Example 97 using7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (80 mg),3-(4-amino-2-methylphenoxy)benzonitrile (108 mg) and pyridinehydrochloride (83 mg).

¹H-NMR (DMSO-d₆) δ 2.18 (3H, s), 7.09 (1H, d, J=8.7 Hz), 7.24 (1H, m),7.37 (1H, m), 7.53-7.59 (2H, m), 7.86 (1H, d, J=8.7 Hz), 7.93 (1H, brs), 8.32 (1H, br s), 8.42 (1H, br s), 9.85 (1H, br s), 12.2 (1H, br s).

Example 138

Production of2-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol(i) Production of2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate

To a solution of 2,2′-oxydiethanol (2.12 g) in pyridine (20 mL) wasadded benzoic anhydride (4.52 g) by small portions under ice-cooling,and the reaction mixture was stirred while warming to room temperaturefor 18 hrs. Pyridine was evaporated under reduced pressure and theobtained residue was diluted with diethyl ether (20 mL). 5% Aqueoussodium hydrogen carbonate solution (100 mL) was added, and the mixturewas extracted with diethyl ether (100 mL×3). The solvent was evaporatedunder reduced pressure, and the obtained residue was subjected to silicagel chromatography (eluent:hexane/ethyl acetate=95/5→40/60). The objectfraction was concentrated under reduced pressure and dried to give2-(2-hydroxyethoxy)ethyl benzoate (2.21 g). To a solution of theobtained 2-(2-hydroxyethoxy)ethyl benzoate (2.10 g) in dichloromethane(10 mL) were added 1-iodopyrrolidine-2,5-dione (2.70 g) andtriphenylphosphine (3.14 g) by small portions under ice-cooling, and themixture was stirred for 14 hrs. The reaction mixture was poured into 5%aqueous sodium hydrogen carbonate solution (100 mL), and extracted withethyl acetate (120 mL×3). The organic layer was washed successively withwater and saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the obtainedresidue was subjected to silica gel chromatography (eluent:hexane/ethylacetate=100/0→60/40). The object fraction was concentrated under reducedpressure and dried to give 2-(2-iodoethoxy)ethyl benzoate (2.05 g) as acolorless transparent oil.

To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.659 g) inN,N-dimethylformamide (5.0 mL) was added cesium carbonate (3.13 g) underice-cooling, and the reaction mixture was stirred while warming to roomtemperature for 15 min. To the reaction mixture was added2-(2-iodoethoxy)ethyl benzoate (1.45 g) prepared above, and the mixturewas stirred at room temperature for 15 hrs. The reaction mixture waspoured into 5% aqueous sodium hydrogen carbonate solution (100 mL), andextracted with ethyl acetate (150 mL×3). The organic layer was washedsuccessively with water and saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the obtained residue was subjected to silica gel chromatography(eluent:hexane/ethyl acetate=95/5->60/40). The object fraction wasconcentrated under reduced pressure and dried to give the title compound(0.822 g) as a colorless transparent oil.

¹H-NMR (CDCl₃) δ 3.718 (2H, dt, J=3.0, 6.6 Hz), 3.887 (2H, t, J=5.1 Hz),4.412 (2H, dt, J=3.0, 6.6 Hz), 4.680 (2H, t, J=5.1 Hz), 6.566 (1H, d,J=3.3 Hz), 7.404-7.462 (2H, m), 7.542-7.600 (2H, m), 7.944-7.982 (2H,m), 8.665 (1H, s).

(ii) Production of2-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethylbenzoate

To a solution of2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate(802 mg) in 1-methyl-2-pyrrolidone (8.0 mL) was added3-chloro-4-[(3-fluorobenzyl)oxy]aniline (745 mg), and the mixture wasstirred in an oil bath at a temperature of 100° C. for 2 hrs. Thereaction mixture was allowed to cool to room temperature, diluted with5% aqueous sodium hydrogen carbonate solution (25 mL), and extractedwith a mixed solvent (50 mL×3) of ethyl acetate/tetrahydrofuran (3/1).The solvent was evaporated under reduced pressure, and the obtainedresidue was subjected to basic silica gel chromatography(eluent:hexane/ethyl acetate=95/5→0/100). The object fraction wasconcentrated under reduced pressure and dried to give the title compound(1141 mg) as a yellow amorphous solid.

¹H-NMR (CDCl₃) δ 3.901-3.931 (2H, m), 4.036 (2H, t, J=4.2 Hz),4.452-4.483 (2H, m), 4.540 (2H, t, J=4.2 Hz), 5.033 (2H, s), 6.590 (1H,d, J=3.0 Hz), 6.704 (1H, d, J=9.0 Hz), 7.005 (1H, td, J=1.8, 7.5 Hz),7.164-7.372 (7H, m), 7.511 (1H, tt, J=1.8, 7.5 Hz), 7.679 (1H, d, J=3.0Hz), 7.769 (1H, t, J=1.8 Hz), 7.788 (1H, t, J=0.6 Hz), 8.431 (1H, s),8.511 (1H, s).

(iii) Production of2-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol

To a solution of2-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethylbenzoate (760 mg) in tetrahydrofuran (7.0 mL) was added 1N aqueoussodium hydroxide solution (7.0 mL), and the mixture was stirred at roomtemperature for 14 hrs. 1N Hydrochloric acid (7.0 mL) was added to thereaction mixture, and the mixture was stirred at room temperature for 10min. and extracted with a mixed solvent (100 mL×3) of ethylacetate/tetrahydrofuran (1/1). The organic layer was washed successivelywith 5% aqueous sodium hydrogen carbonate and saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the obtained residue was subjected to basic silicagel column chromatography (eluent:ethyl acetate/methanol=100/0→90/10).The object fraction was concentrated under reduced pressure. A mixedsolvent of ethanol/isopropyl ether (1/4) was added to the residue, andthe mixture was heated to 80° C. and then allowed to cool to roomtemperature. The resultant precipitate was collected by filtration anddried under reduced pressure to give the title compound (431 mg) aswhite powder crystals.

¹H-NMR (DMSO-d₆) δ 3.471-3.478 (4H, m), 3.817 (2H, t, J=4.6 Hz), 4.616(2H, t, J=4.6 Hz), 4.681-4.712 (1H, m), 5.234 (2H, s), 6.480 (1H, d,J=3.2 Hz), 7.173-7.212 (2H, m), 7.289-7.339 (2H, m), 7.433-7.523 (2H,m), 7.641 (1H, d, J=3.2 Hz), 7.829 (1H, d, J=3.2 Hz), 8.271 (1H, s),8.698 (1H, s).

melting point: 168-169° C.

Example 139

Production of4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]butan-1-ol(i) Production of 4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)butylacetate

To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.768 g) inN,N-dimethylformamide (10 mL) was added cesium carbonate (2.01 g) underice-cooling, and the reaction mixture was stirred while warming to roomtemperature for 15 min. 4-Bromobutyl acetate (1.26 g) was added dropwiseto the reaction mixture, and the mixture was stirred at room temperaturefor 30 hrs. The reaction mixture was poured into 5% aqueous sodiumhydrogen carbonate solution (80 mL), and extracted with ethyl acetate(100 mL×3) The organic layer was washed successively with water andsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the obtained residue wassubjected to silica gel chromatography (eluent:hexane/ethylacetate=95/5→0/100). The object fraction was concentrated under reducedpressure and dried to give the title compound (1.084 g) as a colorlesstransparent oil.

¹H-NMR (CDCl₃) δ 1.636-1.730 (2H, m), 1.874-1.971 (2H, m) 2.047 (3H, s),4.098 (2H, t, J=6.3 Hz), 4.512 (2H, t, J=6.3 Hz), 6.718 (1H, d, J=3.3Hz), 7.482 (1H, d, J=3.3 Hz), 8.690 (1H, s).

(ii) Production of4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]butylacetate

To a solution of 4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)butylacetate (302 mg) in isopropyl alcohol (2.24 mL) was added3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (421 mg), and the mixturewas stirred in an oil bath at a temperature of 100° C. for 3.5 hrs. Thereaction mixture was allowed to cool to room temperature, 5% aqueoussodium hydrogen carbonate solution (35 mL) was added, and the mixturewas extracted with ethyl acetate (50 mL×3). The organic layer was washedsuccessively with water and saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the obtained residue was subjected to basic silica gelchromatography (eluent:hexane/ethyl acetate=95/5→20/80). The objectfraction was concentrated under reduced pressure and dried to give thetitle compound (293 mg) as a white powder.

¹H-NMR (CDCl₃) δ 1.624-1.714 (2H, m), 1.924-2.005 (2H, m), 2.005 (3H,s), 4.108 (2H, t, J=6.0 Hz), 4.342 (2H, t, J=6.0 Hz), 6.573 (1H, d,J=3.3 Hz), 7.054 (1H, s), 7.083-7.471 (7H, m), 7.793 (1H, d, J=3.3 Hz),8.526 (1H, s).

(iii) Production of4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]butan-1-ol

To a solution of4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]butylacetate (281 mg) in tetrahydrofuran (4.0 mL) was added 1N aqueous sodiumhydroxide solution (2.8 mL), and the mixture was stirred at roomtemperature for 4.5 hrs. 1N Aqueous hydrochloric acid solution (2.8 mL)was added, and the mixture was stirred for 15 min. The reaction mixturewas poured into water (50 mL), and the mixture was extracted with ethylacetate (50 mL×3). The organic layer was washed successively with 5%aqueous sodium hydrogen carbonate solution, water and saturated brineand dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the obtained residue was subjected to basicsilica gel chromatography (eluent:hexane/ethyl acetate=95/5→0/100). Theobject fraction was concentrated under reduced pressure and dried.Ethanol/diisopropyl ether (5/95) was added to the residue, and themixture was stirred with heating to 80° C., allowed to cool to roomtemperature, and stood still.

The resultant precipitate was collected by filtration. The obtainedprecipitate was washed with diisopropyl ether and dried under reducedpressure to give the title compound (214 mg) as white powder crystals.

¹H-NMR (DMSO-d₆) δ 1.240-1.331 (2H, m), 1.690-1.782 (2H, m), 3.324-3.361(2H, m), 4.473 (1H, br s), 4.540 (2H, t, J=6.0 Hz), 6.492 (1H, d, J=3.0Hz), 7.200-7.254 (2H, m), 7.303 (1H, d, J=9.0 Hz), 7.472 (1H, d, J=9.0Hz), 7.621 (1H, t, J=9.0 Hz), 7.653-7.713 (2H, m), 7.970 (1H, s), 8.351(1H, s), 8.632 (1H, s).

Example 140

Production of3-(2-chloro-4-{[5-(2-hydroxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl]amino}phenoxy)benzonitrile(i) Production of2-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethylbenzoate

To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (141 mg) inN,N-dimethylformamide (2.5 mL) was added cesium carbonate (358 mg) underice-cooling, and the reaction mixture was stirred while warming to roomtemperature for 15 min. To the reaction mixture was added 2-iodoethylbenzoate (298 mg), and the mixture was stirred at room temperature for15 hrs. The reaction mixture was poured into 5% aqueous sodium hydrogencarbonate solution (50 mL), and extracted with ethyl acetate (50 mL×3).The organic layer was washed successively with water and saturated brineand dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the obtained residue was subjected to silicagel chromatography (eluent:hexane/ethyl acetate=95/5→60/40). The objectfraction was concentrated under reduced pressure and dried to give2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl benzoate (205 mg) as acolorless transparent oil.

The title compound (311 mg) was obtained as a yellow solid by thereaction in the same manner as in Example 42 (ii) using3-(4-amino-2-chlorophenoxy)benzonitrile (211 mg) and a solution of2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl benzoate (205 mg) in1-methyl-2-pyrrolidone (1.3 mL).

¹H-NMR (CDCl₃) δ 4.693 (4H, s), 6.688 (1H, d, J=3.0 Hz), 7.086-7.497(8H, m), 7.609-7.727 (2H, m), 7.962 (2H, d, J=6.9 Hz), 8.024 (2H, d,J=6.9 Hz), 8.569 (1H, s).

(ii) Production of3-(2-chloro-4-{[5-(2-hydroxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl]amino}phenoxy)benzonitrile

The title compound (187 mg) was obtained as a pale-yellow powder by thereaction in the same manner as in Example 138 (iii) using2-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethylbenzoate (310 mg).

¹H-NMR (DMSO-d₆) δ 3.977-3.990 (2H, m), 4.542 (2H, br s), 6.470 (1H, d,J=3.0 Hz), 7.162-7.24 (3H, m), 7.421-7.625 (3H, m), 7.645 (1H, d, J=7.2Hz), 7.989 (1H, d, J=3.0 Hz), 8.078 (1H, d, J=3.0 Hz), 8.368 (1H, s),10.10 (1H, br s).

Example 141

Production of3-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy]benzonitrile(i) Production of2-[2-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethylbenzoate

The title compound (117 mg) was obtained as a pale brown solid by thereaction in the same manner as in Example 138 (ii) using2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate(130 mg) and 3-(4-amino-2-chlorophenoxy)benzonitrile (112 mg).

¹H-NMR (CDCl₃) δ 4.051-4.077 (2H, m), 4.206 (2H, t, J=4.2 Hz),4.582-4.599 (2H, m), 4.610 (2H, t, J=4.2 Hz), 6.781 (1H, d, J=3.0 Hz),6.904 (1H, d, J=9.0 Hz), 7.195 (1H, td, J=1.8, 7.5 Hz), 7.360-7.568 (7H,m), 7.709 (1H, tt, J=1.8, 7.5 Hz), 7.872 (1H, d, J=3.0 Hz), 7.975 (1H,t, J=1.8 Hz), 7.968 (1H, t, J=0.6 Hz), 8.531 (1H, s), 8.671 (1H, s).

(ii) Production of3-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy]benzonitrile

The title compound (52 mg) was obtained as a pale-yellow powder by thereaction in the same manner as in Example 138 (iii) using2-[2-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethylbenzoate (92 mg).

¹H-NMR (DMSO-d₆) δ 3.578-3.693 (4H, m), 3.617 (2H, t, J=4.8 Hz), 4.515(2H, t, J=4.8 Hz), 4.589-4.699 (1H, m), 6.378 (1H, d, J=3.0 Hz),7.153-7.181 (3H, m), 7.411-7.461 (1H, m), 7.553-7.663 (2H, m), 7.840(1H, d, J=3.2 Hz), 8.049 (1H, d, J=3.2 Hz), 8.377 (1H, s), 8.879 (1H,s).

Example 142

Production of2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]-N-(2-hydroxyethyl)acetamide(i) Production of ethyl[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]acetate

To a solution of ethyl (4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)acetate(530 mg) in isopropyl alcohol (4.0 mL) was added3-chloro-4-[(3-fluorobenzyl)oxy]aniline (695 mg), and the mixture wasstirred in an oil bath at a temperature of 100° C. for 2.5 hrs. Thereaction mixture was allowed to cool to room temperature, diluted with5% aqueous sodium hydrogen carbonate solution (25 mL), and extractedwith ethyl acetate (30 mL×3). The organic layer was washed successivelywith water and saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theobtained residue was subjected to basic silica gel chromatography(eluent:hexane/ethyl acetate=95/5→20/80). The object fraction wasconcentrated under reduced pressure and dried to give the title compound(743 mg) as a white solid.

¹H-NMR (CDCl₃) δ 1.298-1.344 (3H, m), 4.338 (2H, q, J=7.2 Hz), 4.938(2H, s), 5.132 (2H, s), 6.616 (1H, d, J=3.4 Hz), 6.935 (1H, d, J=8.8Hz), 6.979-7.056 (1H, m), 7.190-7.263 (3H, m), 7.301-7.426 (2H, m),7.638 (1H, t, J=2.4 Hz), 8.200 (1H, s), 8.499 (1H, br s).

(ii) Production of[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]aceticacid

The title compound (504 mg) was obtained as a pale-purple powder by thereaction in the same manner as in Example 46 using ethyl[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]acetate(730 mg).

¹H-NMR (DMSO-d₆) δ 5.223 (2H, s), 5.282 (2H, s), 6.480 (1H, d, J=3.0Hz), 7.137-7.525 (7H, m), 7.603 (1H, d, J=3.0 Hz), 7.666 (1H, d, J=3.0Hz), 8.299 (1H, s).

(iii) Production of2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]-N-(2-hydroxyethyl)acetamide

The title compound (39 mg) was obtained as a pale-yellow powder by thereaction in the same manner as in Example 36 using[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]aceticacid (103 mg).

¹H-NMR (DMSO-d₆) δ 3.23 (2H, m), 3.46 (2H, m), 4.89 (1H, t, J=4.5 Hz),5.04 (2H, s), 5.22 (2H, s), 6.48 (1H, d, J=3.0 Hz), 7.14-7.24 (2H, m),7.29-7.33 (2H, m), 7.43-7.53 (2H, m), 7.56 (1H, d, J=3.0 Hz), 7.85 (1H,d, J=3.0 Hz), 8.29 (1H, s), 8.97 (1H, br s), 10.08 (1H, br s).

Example 143

Production of3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propan-1-ol

To a solution of 3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propan-1-ol(201 mg) synthesized in Example 53 (ii) in isopropyl alcohol (2.5 mL)was added 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (381 mg), andthe mixture was stirred in an oil bath at a temperature of 100° C. for2.0 hrs. The reaction mixture was allowed to cool to room temperature,diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), andextracted with ethyl acetate (30 mL×3). The organic layer was washedsuccessively with water and saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the obtained residue was subjected to basic silica gelchromatography (eluent:hexane/ethyl acetate=95/5→20/80). The objectfraction was concentrated under reduced pressure and dried.

Ethanol/diisopropyl ether (1/9) was added to the residue, and themixture was stirred with heating to 80° C., allowed to cool to roomtemperature, and stood still. The resultant precipitate was collected byfiltration. The obtained precipitate was washed with diisopropyl etherand dried under reduced pressure to give the title compound (375 mg) aswhite powder crystals.

¹H-NMR (DMSO-d₆) δ 1.953 (2H, t, J=5.7 Hz), 3.380 (2H, t, J=5.7 Hz),4.545 (2H, t, J=6.6 Hz), 5.372 (1H, br s), 6.527 (1H, d, J=3.0 Hz),7.198-7.327 (3H, m), 7.470 (1H, d, J=7.5 Hz), 7.592-7.707 (3H, m), 7.981(1H, d, J=3.0 Hz), 8.354 (1H, s), 9.038 (1H, br s).

Example 144

Production of2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethylcarbamate hydrochloride

To a solution of2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol(84 mg) in a mixed solvent (1.0 mL) of toluene/dichloromethane (1/1) wasadded trichloroacetyl isocyanate (22 μL) under ice-cooling, and themixture was stirred for 3 hrs. To the reaction mixture were addedmethanol (0.2 mL) and potassium carbonate (71 mg), and the mixture wasstirred at room temperature for 12 hrs. The reaction mixture was pouredinto 5% aqueous sodium hydrogen carbonate solution (25 mL), andextracted with ethyl acetate (30 mL×3). The organic layer was washedsuccessively with water and saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the obtained residue was subjected to basic silica gelchromatography (eluent:ethyl acetate/methanol=100/0→95/5). The objectfraction was concentrated under reduced pressure and dried to give2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethylcarbamate (83 mg) as a colorless transparent oil. 4N Hydrochloricacid/ethyl acetate solution was added to the obtained colorlesstransparent oil. After stirring at room temperature for 3 hrs, theresultant precipitate was collected by filtration, washed withdiisopropyl ether, ethyl acetate and ice water, and dried under reducedpressure at 60° C. to give the title compound (57 mg) as a pale-yellowpowder.

¹H-NMR (DMSO-d₆) δ 3.57 (2H, t, J=3.0 Hz), 3.79 (2H, t, J=3.0 Hz), 3.96(2H, t, J=6.0 Hz), 4.64 (2H, t, J=6.0 Hz), 6.48 (2H, br s), 6.56 (1H,s), 7.15-7.23 (2H, m), 7.30-7.34 (2H, m), 7.41 (1H, dd, J=3.0, 9.0 Hz),7.47 (1H, dt, J=6.0, 9.0 Hz), 7.63 (1H, d, J=3.0 Hz), 7.82 (1H, s), 8.28(1H, s), 8.56 (1H, s).

Example 145

Production of2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethanol

A mixture of 2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl benzoate(302 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (288 mg) and1-methyl-2-pyrrolidone (3 mL) was stirred at 120° C. for 2 hrs. Waterand saturated aqueous sodium hydrogen carbonate solution were added tothe reaction mixture and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed successively with water and saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the obtained residue wassubjected to silica gel column chromatography (eluent, ethylacetate:hexane=20:80→100:0). The object fraction was concentrated underreduced pressure. Diethyl ether was added to the residue to allowcrystallization, and diisopropyl ether was added, which was followed byfiltration to give a white powder (286 mg). To a solution of this whitepowder (221 mg) in methanol (5 mL) was added 1N aqueous sodium hydroxidesolution (0.8 mL), and the mixture was stirred at room temperature for 2hrs. Water was added to the reaction mixture and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and ethyl acetate and diisopropylether were added to the obtained residue, which was followed byfiltration to give the title compound (160 mg) as a white powder.

¹H-NMR (CDCl₃) δ 4.16 (2H, t, J=4.4 Hz), 4.38 (2H, t, J=4.4 Hz), 6.12(1H, d, J=3.2 Hz), 6.97 (1H, d, J=3.2 Hz), 7.09 (1H, d, J=8.8 Hz),7.10-7.17 (1H, m), 7.21 (1H, s), 7.32 (1H, d, J=7.7 Hz), 7.43 (1H, t,J=8.0 Hz), 7.52 (1H, dd, J=8.8, 2.6 Hz), 7.84 (1H, d, J=2.6 Hz), 8.24(1H, s), 9.59 (1H, br s).

Example 146

Production of2-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethanol

A mixture of 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethylbenzoate (346 mg), 3-chloro-4-(3-chlorophenoxy)aniline (280 mg) and1-methyl-2-pyrrolidone (3 mL) was stirred at 120° C. for 2 hrs. Waterand saturated aqueous sodium hydrogen carbonate solution were added tothe reaction mixture and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed successively with water and saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the obtained residue wassubjected to silica gel column chromatography (eluent, ethylacetate:hexane=30:70→100:0). The object fraction was concentrated underreduced pressure.

To a solution of the residue (431 mg) in methanol (10 mL) was added 1Naqueous sodium hydroxide solution (1 mL), and the mixture was stirred atroom temperature for 4 hrs. Water was added to the reaction mixture andthe mixture was extracted with ethyl acetate. The ethyl acetate layerwas washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theobtained residue was crystallized from ethyl acetate-diethyl ether togive the title compound (312 mg) as a white powder.

¹H-NMR (CDCl₃) δ 2.05 (1H, br s), 3.71-3.84 (4H, m), 4.03 (2H, t, J=4.5Hz), 4.57 (2H, t, J=4.5 Hz), 6.61 (1H, d, J=3.0 Hz), 6.83-6.88 (1H, m),6.92 (1H, t, J=2.2 Hz), 7.01-7.06 (1H, m), 7.06 (1H, d, J=8.9 Hz),7.19-7.27 (2H, m), 7.61 (1H, dd, J=8.9, 2.6 Hz), 7.89 (1H, d, J=2.6 Hz),8.52 (1H, s), 8.82 (1H, br s).

Example 147

Production of2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol

A mixture of 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethylbenzoate (1.037 g), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (863mg) and 1-methyl-2-pyrrolidone (10 mL) was stirred at 120° C. for 1.5hrs. Water and saturated aqueous sodium hydrogen carbonate solution wereadded to the reaction mixture and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed successively with water andsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the obtained residue wassubjected to silica gel column chromatography (eluent, ethylacetate:hexane=50:50→100:0). The object fraction was concentrated underreduced pressure. To a solution of the residue (1.420 g) in methanol (30mL) was added 1N aqueous sodium hydroxide solution (3 mL), and themixture was stirred at room temperature for 1 hr. The reaction mixturewas concentrated under reduced pressure, water was added to the reactionmixture and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the obtained residue was subjected to silica gel columnchromatography (eluent, methanol:ethyl acetate=0:100→5:95). The objectfraction was concentrated under reduced pressure. The precipitatedcrystals were collected by filtration, and washed with diethyl ether.The crude crystals were recrystallized from ethyl acetate-diisopropylether to give the title compound (933 mg) as a white powder.

¹H-NMR (CDCl₃) δ 1.94 (1H, br s), 3.71-3.85 (4H, m), 4.03 (2H, t, J=4.4Hz), 4.57 (2H, t, J=4.4 Hz), 6.63 (1H, d, J=3.2 Hz), 7.07 (1H, d, J=8.9Hz), 7.08-7.14 (1H, m), 7.19 (1H, s), 7.22 (1H, d, J=3.2 Hz), 7.31 (1H,d, J=7.7 Hz), 7.42 (1H, t, J=8.0 Hz), 7.63 (1H, dd, J=8.9, 2.6 Hz), 7.91(1H, d, J=2.6 Hz), 8.52 (1H, s), 8.83 (1H, br s)

melting point: 130-132° C.

Example 148

Production of2-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol

The title compound (293 mg) was obtained as a white powder by thereaction in the same manner as in Example 146 using2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate(346 mg), 3-chloro-4-[3-(trifluoromethoxy)phenoxy]aniline (334 mg) and1-methyl-2-pyrrolidone (3 mL).

¹H-NMR (CDCl₃) δ 1.95 (1H, br s), 3.71-3.84 (4H, m), 4.03 (2H, t, J=4.5Hz), 4.57 (2H, t, J=4.5 Hz), 6.62 (1H, d, J=3.2 Hz), 6.80-6.95 (3H, m),7.08 (1H, d, J=8.8 Hz), 7.21 (1H, d, J=3.2 Hz), 7.30 (1H, t, J=8.2 Hz),7.62 (1H, dd, J=8.8, 2.6 Hz), 7.90 (1H, d, J=2.6 Hz), 8.52 (1H, s), 8.82(1H, br s).

Example 149

Production of1-{3-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy]phenyl}ethanone

The title compound (493 mg) was obtained as a white powder by thereaction in the same manner as in Example 146 using2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate(692 mg), 1-[3-(4-amino-2-chlorophenoxy)phenyl]ethanone (576 mg) and1-methyl-2-pyrrolidone (5 mL).

¹H-NMR (CDCl₃) δ 1.97 (1H, br s), 2.58 (3H, s), 3.71-3.84 (4H, m), 4.03(2H, t, J=4.4 Hz), 4.58 (2H, t, J=4.4 Hz), 6.63 (1H, d, J=3.2 Hz), 7.06(1H, d, J=8.9 Hz), 7.15-7.20 (1H, m), 7.22 (1H, d, J=3.2 Hz), 7.41 (1H,t, J=7.9 Hz), 7.48-7.51 (1H, m), 7.61 (1H, dd, J=8.9, 2.6 Hz), 7.62-7.67(1H, m), 7.90 (1H, d, J=2.6 Hz), 8.52 (1H, s), 8.80 (1H, br s).

Example 150

Production of1-{3-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy]phenyl}ethanol

To a solution of1-{3-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy]pheny}ethanone(233 mg) in methanol (5 mL) was added sodium borohydride (38 mg), andthe mixture was stirred at room temperature for 2 hrs. Water was addedto the reaction mixture and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the obtained residue was crystallized from ethylacetate-diethyl ether to give the title compound (225 mg) as a whitepowder.

¹H-NMR (CDCl₃) δ 2.47 (3H, d, J=6.4 Hz), 3.67-3.77 (4H, m), 4.00 (2H, t,J=4.4 Hz), 4.58 (2H, t, J=4.4 Hz), 4.84 (1H, q, J=6.4 Hz), 6.62 (1H, d,J=3.3 Hz), 6.85-6.90 (1H, m), 6.96-7.00 (1H, m), 7.01-7.09 (2H, m),7.24-7.32 (2H, m), 7.52 (1H, dd, J=8.9, 2.6 Hz), 7.86 (1H, d, J=2.6 Hz),8.45 (1H, s).

Example 151

Production of2-[2-(4-{[3-chloro-4-(pyrimidin-5-yloxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethanol

The title compound (63 mg) was obtained as a white powder by thereaction in the same manner as in Example 146 using2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate(346 mg), 3-chloro-4-(pyrimidin-5-yloxy)aniline (360 mg) and1-methyl-2-pyrrolidone (3 mL).

¹H-NMR (CDCl₃) δ 2.08 (1H, br s), 3.72-3.84 (4H, m), 4.03 (2H, t, J=4.4Hz), 4.58 (2H, t, J=4.4 Hz), 6.63 (1H, d, J=3.1 Hz), 7.12 (1H, d, J=8.7Hz), 7.23 (1H, d, J=3.1 Hz), 7.67 (1H, dd, J=8.7, 2.6 Hz), 7.95 (1H, d,J=2.6 Hz), 8.43 (2H, s), 8.52 (1H, s), 8.89 (1H, br s), 8.94 (1H, s).

Example 152

Production of2-(2-{4-[(3-chloro-4-{[2-(trifluoromethyl)benzyl]oxy}phenyl)amino]-5H-pyrrolo[3,2-d]pyrimidin-5-yl}ethoxy)ethanol

The title compound (276 mg) was obtained as a white powder by thereaction in the same manner as in Example 146 using2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate(277 mg), 3-chloro-4-{[2-(trifluoromethyl)benzyl]oxy}aniline (241 mg)and 1-methyl-2-pyrrolidone (3 mL).

¹H-NMR (CDCl₃) δ 2.02 (1H, br s), 3.68-3.81 (4H, m), 4.00 (2H, t, J=4.4Hz), 4.53 (2H, t, J=4.4 Hz), 5.34 (2H, s), 6.58 (1H, d, J=3.2 Hz), 6.93(1H, d, J=8.8 Hz), 7.17 (1H, d, J=3.2 Hz), 7.42 (1H, t, J=7.7 Hz), 7.49(1H, dd, J=8.8, 2.6 Hz), 7.60 (1H, t, J=7.7 Hz), 7.69 (1H, d, J=7.7 Hz),7.76 (1H, d, J=2.6 Hz), 7.89 (1H, d, J=7.7 Hz), 8.46 (1H, s), 8.57 (1H,br s).

Example 153

Production of2-(2-{4-[(3-chloro-4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)amino]-5H-pyrrolo[3,2-d]pyrimidin-5-yl}ethoxy)ethanol

The title compound (393 mg) was obtained as a white powder by thereaction in the same manner as in Example 146 using2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate(346 mg), 3-chloro-4-{[3-(trifluoromethyl)benzyl]oxy}aniline (302 mg)and 1-methyl-2-pyrrolidone (3 mL).

¹H-NMR (CDCl₃) δ 2.03 (1H, br s), 3.68-3.80 (4H, m), 4.00 (2H, t, J=4.4Hz), 4.54 (2H, t, J=4.4 Hz), 5.17 (2H, s), 6.59 (1H, d, J=3.1 Hz), 6.95(1H, d, J=8.8 Hz), 7.17 (1H, d, J=3.1 Hz), 7.48-7.62 (3H, m), 7.66-7.76(3H, m), 8.46 (1H, s), 8.58 (1H, br s).

Example 154

Production of5-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]pentan-1-ol(i) Production of 5-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)pentylacetate

A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.50 g),5-bromopentyl acetate (0.71 mL), cesium carbonate (1.59 g) andN,N-dimethylformamide (5.0 mL) was stirred at 40° C. for 4 days. Waterwas added to the reaction system and the mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine and dried over magnesium sulfate. After concentration underreduced pressure, the residue was separated and purified by silica gelcolumn chromatography (eluent, ethyl acetate:hexane=1:3→6:4) to give thetitle compound (637 mg) as a white solid.

¹H-NMR (CDCl₃) δ: 1.33-1.46 (2H, m), 1.61-1.72 (2H, m), 1.84-1.97 (2H,m), 2.04 (3H, s), 4.05 (2H, t, J=6.6 Hz), 4.48 (2H, t, J=7.5 Hz), 6.71(1H, d, J=3.3 Hz), 7.46 (1H, d, J=3.3 Hz), 8.69 (1H, s).

(ii) Production of5-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]pentan-1-ol

A solution of 5-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)pentyl acetate(200 mg) and 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (265 mg) inisopropyl alcohol (3.5 mL) was stirred at 80° C. for 14 hrs. 1N Aqueoussodium hydroxide solution (2.1 mL) was added at 0° C., and the mixturewas stirred at room temperature for 1 hr. 1N Hydrochloric acid (2.0 mL)was added to the reaction system, and the mixture was extracted withethyl acetate. The organic layer was washed with aqueous sodium hydrogencarbonate and saturated brine and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by silica gel column chromatography (eluent, ethylacetate→ethyl acetate:methanol=1:19) to give a colorless solid.Recrystallization from ethyl acetate-hexane gave the title compound (275mg) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.35 (1H, t, J=4.7 Hz), 1.50-1.69 (4H, m), 1.92-2.05(2H, m), 3.63-3.71 (2H, m), 4.32 (2H, t, J=7.4 Hz), 6.59 (1H, d, J=3.3Hz), 6.70 (1H, s), 7.08 (1H, d, J=8.7 Hz), 7.09-7.12 (1H, m), 7.15-7.27(2H, m), 7.30-7.35 (1H, m), 7.40-7.43 (1H, m), 7.47 (1H, dd, J=8.7, 2.7Hz), 7.82 (1H, d, J=2.7 Hz), 8.53 (1H, s).

Example 155

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-hydroxyacetamide(i) Production of tert-butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate

The title compound (687 mg) was obtained as a colorless solid by thereaction in the same manner as in Example 154 (i) using4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.50 g), tert-butyl2-bromoethylcarbamate (0.95 g), cesium carbonate (1.59 g) andN,N-dimethylformamide (10 ml).

¹H-NMR (CDCl₃) δ: 1.31-1.46 (9H, m), 3.55 (2H, dt, J=6.0, 6.0 Hz),4.51-4.68 (3H, m), 6.74 (1H, d, J=3.2 Hz), 7.47 (1H, d, J=3.2 Hz), 8.71(1H, s).

(ii) Production of tert-butyl{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate

A solution of tert-butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (712 mg)and 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (830 mg) in isopropylalcohol (7.1 mL) was stirred at 80° C. for 12 hrs. Aqueous sodiumhydrogen carbonate was added to the reaction system and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over magnesium sulfate. After concentrationunder reduced pressure, the residue was separated and purified by silicagel column chromatography (eluent, hexane:ethyl acetate=1:1-+ethylacetate) to give the title compound (1.12 g) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 3.43-3.54 (2H, m), 4.43-4.51 (2H, m),5.10 (1H, t, J=5.6 Hz), 6.60 (1H, d, J=3.3 Hz), 7.07 (1H, m), 7.09-7.14(1H, m), 7.16-7.22 (2H, m), 7.25-7.30 (1H, m), 7.37-7.45 (1H, m), 7.89(1H, dd, J=8.7, 2.4 Hz), 8.02 (1H, d, J=2.4 Hz), 8.50 (1H, s), 8.64 (1H,br s).

(iii) Production of5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride

A mixture of tert-butyl{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate(1.12 g), 2N hydrochloric acid (15 mL) and tetrahydrofuran (30 mL) wasstirred at 60° C. for 20 hrs. The solvent was evaporated under reducedpressure, ethanol was added, and the mixture was further concentrated.The precipitated crystals were collected by filtration and the crystalswere washed with ethyl acetate to give the title compound (1.07 g) aspale-yellow crystals.

¹H-NMR (DMSO-d₆) δ: 3.21-3.35 (2H, m), 4.92-5.02 (2H, m), 6.71-6.76 (1H,m), 7.24-7.32 (2H, m), 7.37 (1H, d, J=9.0 Hz), 7.50-7.56 (1H, m),7.64-7.71 (2H, m), 7.91-7.97 (1H, m), 7.98-8.06 (1H, m), 8.13-8.26 (3H,m), 8.71 (1H, br s), 9.88-9.99 (1H, m).

(iv) Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-hydroxyacetamide

A mixture of5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (105 mg), glycolic acid (44 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (167 mg),1-hydroxybenzotriazole monohydrate (133 mg), triethylamine (0.40 mL) andN,N-dimethylformamide (5.0 mL) was stirred at room temperature for 3days. Water was added to the reaction system and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by basic silica gel column chromatography (eluent, ethylacetate→methanol:ethyl acetate=1:9) to give the title compound (108 mg)as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.93-3.09 (1H, m), 3.59-3.73 (2H, m), 4.24 (2H, s),4.43-4.53 (2H, m), 6.59 (1H, d, J=3.3 Hz), 7.07 (1H, d, J=8.7 Hz),7.09-7.46 (6H, m), 7.72 (1H, dd, J=8.7, 2.4 Hz), 8.06 (1H, d, J=2.4 Hz),8.49 (1H, s), 8.57 (1H, s).

Example 156

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide(i) Production of tert-butyl{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate

A solution of tert-butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (100 mg),3-chloro-4-[3-(trifluoromethoxy)phenoxy]aniline (153 mg) in isopropylalcohol (1.5 mL) was stirred at 80° C. for 12 hrs. Aqueous sodiumhydrogen carbonate was added to the reaction system and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over magnesium sulfate. After concentrationunder reduced pressure, the residue was separated and purifed by silicagel column chromatography (eluent, hexane:ethyl acetate=1:1→ethylacetate) to give the title compound (173 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 3.45-3.54 (2H, m), 4.43-4.52 (2H, m),5.01-5.08 (1H, m), 6.61 (1H, d, J=3.0 Hz), 6.80-6.95 (3H, m), 7.09 (1H,d, J=8.7 Hz), 7.19 (1H, d, J=3.0 Hz), 7.29-7.34 (1H, m), 7.90 (1H, dd,J=8.7, 2.7 Hz), 8.03 (1H, d, J=2.7 Hz), 8.52 (1H, s), 8.62 (1H, br s).

(ii) Production of5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride

A mixture of tert-butyl{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate(173 mg), 2N hydrochloric acid (2.5 mL) and tetrahydrofuran (5.0 mL) wasstirred at 60° C. for 6 hrs. Ethanol was added to the reaction system.The solvent was evaporated under reduced pressure. Ethanol was added tothe concentrate, and the mixture was further concentrated under reducedpressure. The residual crystals were collected by filtration and thecrystals were washed with ethyl acetate to give the title compound (155mg) as pale-yellow crystals.

¹H-NMR (DMSO-d₆) δ: 3.21-3.34 (2H, m), 4.89-5.00 (2H, m), 6.74 (1H, d,J=2.4 Hz), 6.94-7.01 (2H, m), 7.16 (1H, d, J=8.7 Hz), 7.36 (1H, d, J=9.0Hz), 7.51-7.57 (1H, m), 7.62-7.69 (1H, m), 7.90-7.95 (1H, m), 7.99-8.05(1H, m), 8.12-8.27 (3H, m), 8.71 (1H, s), 9.92 (1H, br s).

(iii) Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide

A mixture of5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (160 mg), 2-(methylsulfonyl)acetic acid (82.3 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (171 mg),1-hydroxybenzotriazole monohydrate (137 mg), triethylamine (0.42 mL) andN,N-dimethylformamide (5.0 mL) was stirred at room temperature for 20hrs. Water was added to the reaction system and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by basic silica gel column chromatography (eluent, ethylacetate→ethyl acetate: methanol=4:1) and crystallization fromethanol-ethyl acetate-diisopropyl ether to give the title compound (112mg) as pale-yellow crystals.

¹H-NMR (CDCl₃) δ: 3.12 (3H, s), 3.64-3.76 (2H, m), 3.99 (2H, s),4.34-4.52 (2H, m), 6.62 (1H, d, J=3.0 Hz), 6.81-6.84 (1H, m), 6.86-6.95(2H, m), 7.08 (1H, d, J=8.7 Hz), 7.17-7.24 (2H, m), 7.29-7.34 (1H, m),7.76 (1H, dd, J=8.7, 2.7 Hz), 7.95 (1H, d, J=2.7 Hz), 8.18 (1H, s), 8.51(1H, s).

melting point: 133-135° C.

Example 157

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-methoxyacetamide

The title compound (120 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 155 (iv) using5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (150 mg), methoxyacetic acid (52 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (166 mg),1-hydroxybenzotriazole monohydrate (133 mg), triethylamine (0.40 mL) andN,N-dimethylformamide (5.0 mL).

¹H-NMR (CDCl₃) δ: 3.44 (3H, s), 3.60-3.71 (2H, m), 4.00 (2H, s),4.44-4.53 (2H, m), 6.62 (1H, d, J=3.0 Hz), 7.02-7.15 (3H, m), 7.19 (1H,d, J=3.0 Hz), 7.22-7.35 (2H, m), 7.38-7.45 (1H, m), 7.74 (1H, dd, J=8.7,2.4 Hz), 8.07 (1H, d, J=2.4 Hz), 8.52 (1H, s), 8.55 (1H, s).

Example 158

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxy-3-methylbutanamide

A mixture of5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (150 mg), 3-hydroxy-3-methylbutyric acid (68 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (166 mg),1-hydroxybenzotriazole monohydrate (133 mg), triethylamine (0.40 mL) andN,N-dimethylformamide (5.0 mL) was stirred at room temperature for 5days. Water was added to the reaction system and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by basic silica gel column chromatography (eluent, ethylacetate→ethyl acetate:methanol=9:1). Crystallization from ethylacetate-diisopropyl ether gave the title compound (122 mg) as colorlesscrystals.

¹H-NMR (CDCl₃) δ: 1.33 (6H, s), 2.49 (2H, s), 2.65-2.77 (1H, m),3.57-3.68 (2H, m), 4.44-4.53 (2H, m), 6.61 (1H, d, J=3.0 Hz), 6.93-7.01(1H, m), 7.07 (1H, d, J=9.0 Hz), 7.09-7.15 (1H, m), 7.19 (1H, d, J=3.0Hz), 7.23-7.35 (2H, m), 7.40-7.45 (1H, m), 7.77 (1H, dd, J=9.0, 2.7 Hz),8.08 (1H, d, J=2.7 Hz), 8.52 (1H, s), 8.66 (1H, s).

melting point: 167-169° C.

Example 159

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-hydroxy-2-methylpropanamide

To a suspension of5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (150 mg) and triethylamine (0.40 mL) in tetrahydrofuran(5.0 mL) was added 1-chlorocarbonyl-1-methylethyl acetate (0.12 mL) atroom temperature. After stirring at room temperature for 3 days, aqueoussodium hydrogen carbonate was added, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover magnesium sulfate and concentrated under reduced pressure. To asolution of the residue in ethanol (3.0 mL) was added 1N aqueous sodiumhydroxide solution (1.5 mL) at room temperature. After stirring at roomtemperature for 24 hrs, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overmagnesium sulfate and concentrated under reduced pressure, and theresidue was separated and purified by basic silica gel columnchromatography (eluent, ethyl acetate→ethyl acetate:methanol=9:1) togive the title compound (133 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.49 (6H, s), 2.12-2.27 (1H, m), 3.56-3.67 (2H, m),4.42-4.52 (2H, m), 6.61 (1H, d, J=3.3 Hz), 7.06 (1H, d, J=9.0 Hz),7.08-7.14 (1H, m), 7.15-7.43 (5H, m), 7.86 (1H, dd, J=9.0, 2.7 Hz), 8.10(1H, d, J=2.7 Hz), 8.51 (1H, s), 8.72 (1H, s).

Example 160

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide

A mixture of5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (150 mg), 2-(methylsulfonyl)acetic acid (79.6 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (166 mg),1-hydroxybenzotriazole monohydrate (133 mg), triethylamine (0.40 mL) andN,N-dimethylformamide (5.0 mL) was stirred at room temperature for 20hrs. Water was added to the reaction system and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by basic silica gel column chromatography (eluent, ethylacetate→ethyl acetate:methanol=4:1). Crystallization from ethylacetate-diisopropyl ether gave the title compound (128 mg) as colorlesspowder crystals.

¹H-NMR (CDCl₃) δ: 3.12 (3H, s), 3.64-3.75 (2H, m), 3.98 (2H, s),4.43-4.53 (2H, m), 6.62 (1H, d, J=3.0 Hz), 7.07 (1H, d, J=9.0 Hz),7.09-7.15 (1H, m), 7.18-7.33 (4H, m), 7.40-7.45 (1H, m), 7.77 (1H, dd,J=9.0, 2.7 Hz), 7.96 (1H, d, J=2.7 Hz), 8.19 (1H, s), 8.51 (1H, s).

melting point: 177-178° C.

Example 161

Production of5-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]-3-methylpentane-1,3-diol(i) Production of 3,5-dihydroxy-3-methylpentyl benzoate

A solution of 3-methyl-1,3,5-pentanetriol (21.9 g), benzoic anhydride(7.39 g), pyridine (4.0 mL) and 4-(N,N-dimethylamino)pyridine (0.39 g)in acetonitrile (200 mL) was stirred at room temperature for 2 days.After concentration under reduced pressure, water was added, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over magnesium sulfate and concentratedunder reduced pressure, and the residue was separated and purified bysilica gel column chromatography (eluent, hexane:ethylacetate=1:1->ethyl acetate) to give the title compound (4.27 g) as acolorless oil.

¹H-NMR (CDCl₃) δ: 1.36 (3H, s), 1.72-1.81 (1H, m), 1.86-2.13 (3H, m),2.47 (1H, t, J=4.7 Hz), 2.89 (1H, s), 3.85-4.02 (2H, m), 4.52 (2H, t,J=6.8 Hz), 7.42-7.48 (2H, m), 7.54-7.60 (1H, m), 8.00-8.04 (2H, m).

(ii) Production of 5-bromo-3-hydroxy-3-methylpentyl benzoate

To a solution of 3,5-dihydroxy-3-methylpentyl benzoate (1.0 g) andcarbon tetrabromide (2.78 g) in tetrahydrofuran (30 mL) was addeddropwise a solution of triphenylphosphine (2.20 g) in tetrahydrofuran(10 mL) under ice-cooling. After stirring at room temperature for 3days, water was added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over magnesiumsulfate and concentrated under reduced pressure, and the residue wasseparated and purified by silica gel column chromatography (eluent,hexane:ethyl acetate=9:1→6:4) to give the title compound (979 mg) as acolorless oil.

¹H-NMR (CDCl₃) δ: 1.32 (3H, s), 1.78 (1H, s), 1.97-2.02 (2H, m),2.11-2.23 (2H, m), 3.53 (2H, t, J=8.1 Hz), 4.51 (2H, t, J=6.5 Hz),7.42-7.48 (2H, m), 7.55-7.60 (1H, m), 8.00-8.04 (2H, m).

(iii) Production of5-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-3-hydroxy-3-methylpentylbenzoate

The title compound (773 mg) was obtained as a colorless oil by thereaction in the same manner as in Example 154 (i) using4-chloro-5H-pyrrolo[3,2-d]pyrimidine (400 mg),5-bromo-3-hydroxy-3-methylpentyl benzoate (979 mg), cesium carbonate(0.94 g) and N,N-dimethylformamide (10 mL).

¹H-NMR (CDCl₃) δ: 1.41 (3H, s), 1.91 (1H, s), 2.01-2.13 (4H, m), 4.54(2H, t, J=6.6 Hz), 4.59-4.76 (2H, m), 6.71 (1H, d, J=3.0 Hz), 7.40-7.46(2H, m), 7.51 (1H, d, J=3.0 Hz), 7.54-7.60 (1H, m), 7.98-8.01 (2H, m),8.69 (1H, s).

(iv) Production of5-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]-3-methylpentane-1,3-diol

The title compound (223 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 154 (ii) using5-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-3-hydroxy-3-methylpentylbenzoate (250 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (230mg), isopropyl alcohol (1.5 mL) and 1N aqueous sodium hydroxide solution(2.0 mL).

¹H-NMR (CDCl₃) δ: 1.35 (3H, s), 1.62-1.71 (1H, m), 1.89-2.22 (4H, m),3.93-4.18 (2H, m), 4.54-4.65 (3H, m), 6.56 (1H, d, J=3.0 Hz), 7.04 (1H,d, J=8.7 Hz), 7.08-7.14 (1H, m), 7.19-7.25 (2H, m), 7.29-7.35 (1H, m),7.39-7.44 (1H, m), 7.61 (1H, dd, J=8.7, 2.7 Hz), 7.93 (1H, d, J=2.7 Hz),8.49 (1H, s), 8.52 (1H, br s).

Example 162

Production of2-({2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}thio)ethanol(i) Production of 2-[(2-hydroxyethyl)thio]ethyl benzoate

A solution of 2-mercaptoethanol (1.52 mL), 2-iodoethyl benzoate (6.00 g)and ethyldiisopropylamine (4.53 mL) in N,N-dimethylformamide (60 mL) wasstirred at 40° C. for 3 days. Water was added to the reaction system andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over magnesium sulfate andconcentrated under reduced pressure. The residue was separated andpurified by silica gel column chromatography (eluent, hexane:ethylacetate=4:1→3:7) to give the title compound (3.77 g) as an orange oil.

¹H-NMR (CDCl₃) δ: 2.15 (1H, t, J=6.0 Hz), 2.83 (2H, t, J=5.9 Hz), 2.92(2H, t, J=6.8 Hz), 3.79 (2H, dt, J=6.0, 6.0 Hz), 4.50 (2H, t, J=6.8 Hz),7.43-7.48 (2H, m), 7.55-7.61 (1H, m), 8.03-8.08 (2H, m).

(ii) Production of 2-[(2-bromoethyl)thio]ethyl benzoate

The title compound (966 mg) was obtained as a colorless oil by thereaction in the same manner as in Example 161 (ii) using2-[(2-hydroxyethyl)thio]ethyl benzoate (1.0 g), carbon tetrabromide(2.20 g), triphenylphosphine (1.74 g) and dichloromethane (50 mL).

¹H-NMR (CDCl₃) δ: 2.95 (2H, t, J=6.8 Hz), 3.02-3.08 (2H, m), 3.50-3.56(2H, m), 4.49 (2H, t, J=6.8 Hz), 7.43-7.48 (2H, m), 7.55-7.61 (1H, m),8.03-8.06 (2H, m).

(iii) Production of2-{[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]thio}ethylbenzoate

The title compound (790 mg) was obtained as a colorless oil by thereaction in the same manner as in Example 154 (i) using4-chloro-5H-pyrrolo[3,2-d]pyrimidine (420 mg),2-[(2-bromoethyl)thio]ethyl benzoate (966 mg), cesium carbonate (1.34 g)and N,N-dimethylformamide (4.2 mL).

¹H-NMR (CDCl₃) δ: 2.81 (2H, t, J=6.8 Hz), 3.08 (2H, t, J=6.9 Hz), 4.45(2H, t, J=6.8 Hz), 4.69 (2H, t, J=6.9 Hz), 6.73 (1H, d, J=3.3 Hz),7.39-7.46 (2H, m), 7.53-7.62 (2H, m), 7.96-8.06 (2H, m), 8.71 (1H, s).

(iv) Production of2-({2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}thio)ethanol

The title compound (420 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 154 (ii) using2-{[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]thio}ethylbenzoate (505 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (480mg), isopropyl alcohol (10 mL) and 1N aqueous sodium hydroxide solution(3.0 mL).

¹H-NMR (CDCl₃) δ: 1.92-2.00 (1H, m), 2.52 (2H, t, J=5.6 Hz), 3.13 (2H,t, J=6.5 Hz), 3.65-3.75 (2H, m), 4.61 (2H, t, J=6.5 Hz), 6.67 (1H, d,J=3.3 Hz), 7.08 (1H, d, J=8.7 Hz), 7.09-7.13 (1H, m), 7.18-7.23 (1H, m),7.29 (1H, d, J=3.3 Hz), 7.32-7.35 (1H, m), 7.41-7.46 (1H, m), 7.51 (1H,dd, J=8.7, 2.7 Hz), 7.77 (1H, d, J=2.7 Hz), 7.80 (1H, s), 8.55 (1H, s).

Example 163

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-N-methyl-2-(methylsulfonyl)acetamide(i) Production of tert-butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]methylcarbamate

To a solution of 2-(methylamino)ethanol (1.00 g) in tetrahydrofuran (10mL) was added di-tert-butyl dicarbonate (3.60 mL) at room temperature.After stirring at room temperature for 2 hrs, the mixture wasconcentrated under reduced pressure. To a solution of the residue andtriethylamine (3.71 mL) in tetrahydrofuran (50 mL) was added dropwisemethanesulfonyl chloride (1.55 mL) at 0° C., and the mixture was stirredat 0° C. for 1 hr. Aqueous sodium hydrogen carbonate was added to thereaction system and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over magnesiumsulfate and concentrated under reduced pressure to give a colorless oil.

The title compound (902 mg) was obtained as a pale-yellow oil by thereaction in the same manner as in Example 154 (i) using the obtainedoil, 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.34 g), cesium carbonate(5.69 g) and N,N-dimethylformamide (20 mL).

¹H-NMR (CDCl₃) δ: 1.12 (4.5H, s), 1.43 (4.5H, m), 2.55 (1.5H, s), 2.81(1.5H, s), 3.58-3.60 (2H, m), 4.54-4.69 (2H, m), 6.73 (1H, d, J=3.0 Hz),7.29-7.35 (0.5H, m), 7.38-7.46 (0.5H, m), 8.71 (1H, s).

(ii) Production of tert-butyl{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}methylcarbamate

The title compound (622 mg) was obtained as a colorless amorphous solidby the reaction in the same manner as in Example 155 (ii) usingtert-butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]methylcarbamate (450mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (500 mg) andisopropyl alcohol (4.5 mL).

¹H-NMR (CDCl₃) δ: 1.51 (9H, s), 3.01 (3H, s), 3.51-3.59 (2H, m),4.41-4.51 (2H, m), 6.60 (1H, d, J=3.0 Hz), 7.06 (1H, d, J=8.7 Hz),7.08-7.13 (1H, m), 7.15-7.24 (2H, m), 7.30 (1H, d, J=8.4 Hz), 7.38-7.44(1H, m), 7.85-7.93 (1H, m), 7.99-8.04 (1H, m), 8.50 (1H, s), 8.82 (1H,s).

(iii) Production ofN-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-[2-(methylamino)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride

The title compound (538 mg) was obtained as pale-yellow crystals by thereaction in the same manner as in Example 155 (iii) using tert-butyl{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}methylcarbamate(622 mg), 2N hydrochloric acid (10 mL) and tetrahydrofuran (20 mL).

¹H-NMR (DMSO-d₆) δ: 2.54 (3H, t, J=5.3 Hz), 3.32-3.44 (2H, m), 5.01-5.15(2H, m), 6.74 (1H, d, J=3.3 Hz), 7.22-7.27 (2H, m), 7.36 (1H, d, J=8.7Hz), 7.51 (1H, d, J=8.4 Hz), 7.60-7.69 (2H, m), 7.91-7.96 (1H, m),8.01-8.07 (1H, m), 8.72 (1H, s), 9.00-9.18 (2H, m), 10.06 (1H br s).

(iv) Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-N-methyl-2-(methylsulfonyl)acetamide

The title compound (131 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 155 (iv) usingN-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-[2-(methylamino)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (170 mg), 2-(methylsulfonyl)acetic acid (88 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (183 mg),1-hydroxybenzotriazole monohydrate (146 mg), triethylamine (0.44 mL) andN,N-dimethylformamide (5.0 mL).

¹H-NMR (CDCl₃) δ: 3.17 (3H, s), 3.34 (3H, s), 3.75-3.84 (2H, m), 4.18(2H, s), 4.43-4.52 (2H, m), 6.64 (1H, d, J=3.0 Hz), 7.08 (1H, d, J=8.7Hz), 7.10-7.16 (1H, m), 7.17-7.25 (2H, m), 7.32-7.37 (1H, m), 7.41-7.46(1H, m), 7.86 (1H, dd, J=8.7, 2.7 Hz), 7.96 (1H, d, J=2.7 Hz), 8.46 (1H,s), 8.53 (1H, s).

Example 164

Production of2-({2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}sulfinyl)ethanol

To a solution of2-({2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}thio)ethanol(100 mg) in dichloromethane (10 mL) was added dropwise a 70% solution of3-chloroperbenzoic acid (58 mg) in dichloromethane (5.0 mL) at −78° C.The mixture was stirred at −78° C. for 1 hr, and aqueous sodiumthiosulfate solution was added. After stirring at room temperature for0.5 hr, the mixture was extracted with ethyl acetate. The organic layerwas washed with saturated brine and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by silica gel column chromatography (eluent, ethylacetate→ethyl acetate:methanol=4:1) to give the title compound (87 mg)as colorless crystals.

¹H-NMR (DMSO-d₆) δ: 2.78-3.01 (2H, m), 3.27-3.40 (1H, m), 3.42-3.58 (1H,m), 3.71-3.79 (2H, m), 4.80-4.90 (2H, m), 5.02-5.09 (1H, m), 6.58-6.63(1H, m), 7.16-7.25 (2H, m), 7.27-7.31 (1H, m), 7.44-7.50 (1H, m),7.59-7.64 (1H, m), 7.66-7.72 (1H, m), 7.74-7.82 (1H, m), 7.96-8.03 (1H,m), 8.37 (1H, s), 9.38 (1H, s).

Example 165

Production of2-({2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}sulfonyl)ethanol

To a solution of2-({2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}thio)ethanol(150 mg), titanium tetraisopropoxide (43 μL), methanol (24 μL) and water(10 μL) in dichloromethane was stirred at room temperature for 30 min.70% Aqueous tert-butyl hydroperoxide solution (0.12 mL) was added to thereaction system, and the mixture was stirred at room temperature for 2days. An aqueous sodium thiosulfate solution was added to the reactionsystem, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over magnesium sulfate andconcentrated under reduced pressure, and the residue was separated andpurified by silica gel column chromatography (eluent, ethylacetate→ethyl acetate:methanol=4:1) to give the title compound (118 mg)as colorless crystals.

¹H-NMR (DMSO-d₆) δ: 3.09-3.15 (2H, m), 3.62-3.75 (4H, m), 4.92-5.02 (2H,m), 5.09-5.15 (1H, m), 6.50-6.57 (1H, m), 7.16-7.32 (3H, m), 7.45-7.48(1H, m), 7.58-7.74 (3H, m), 7.91-7.97 (1H, m), 8.37 (1H, br s),8.69-8.79 (1H, m)

Example 166

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-N-methyl-2-(methylsulfonyl)acetamide(i) Production of tert-butyl{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}methylcarbamate

The title compound (665 mg) was obtained as a colorless amorphous solidby the reaction in the same manner as in Example 155 (ii) usingtert-butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]methylcarbamate (463mg), 3-chloro-4-[3-(trifluoromethoxy)phenoxy]aniline (679 mg) andisopropyl alcohol (5.0 mL).

¹H-NMR (CDCl₃) δ: 1.51 (9H, s), 3.01 (3H, s), 3.48-3.61 (2H, m),4.42-4.50 (2H, m), 6.60 (1H, d, J=3.2 Hz), 6.80-6.83 (1H, m), 6.86-6.95(2H, m), 7.08 (1H, d, J=8.7 Hz), 7.20 (1H, d, J=3.2 Hz), 7.28-7.33 (1H,m), 7.85-7.95 (1H, m), 7.99-8.05 (1H, m), 8.51 (1H, s), 8.81 (1H, br s).

(ii) Production ofN-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5-[2-(methylamino)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride

The title compound (557 mg) was obtained as pale-yellow crystals by thereaction in the same manner as in Example 155 (iii) using tert-butyl{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}methylcarbamate(665 mg), 2N hydrochloric acid (10 mL) and tetrahydrofuran (20 mL).

¹H-NMR (DMSO-d₆) δ: 2.52-2.66 (2H, m)), 3.29-3.45 (2H, m), 5.03-5.15(2H, m), 6.75 (1H, d, J=3.0 Hz), 6.91-7.00 (2H, m), 7.11-7.18 (1H, m),7.35 (1H, d, J=8.7 Hz), 7.51-7.57 (1H, m), 7.63-7.69 (1H, m), 7.91-7.96(1H, m), 8.06 (1H, d, J=3.3 Hz), 8.73 (1H, s), 9.06-9.26 (2H, m), 10.11(1H, br s)

(iii) Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-N-methyl-2-(methylsulfonyl)acetamide

The title compound (147 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 155 (iv) usingN-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5-[2-(methylamino)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (170 mg), 2-(methylsulfonyl)acetic acid (87 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (179 mg),1-hydroxybenzotriazole monohydrate (143 mg), triethylamine (0.43 mL) andN,N-dimethylformamide (5.0 ml).

¹H-NMR (CDCl₃) δ: 3.17 (3H, s), 3.34 (3H, s), 3.75-3.84 (2H, m), 4.18(2H, s), 4.43-4.52 (2H, m), 6.64 (1H, d, J=3.0 Hz), 7.08 (1H, d, J=8.7Hz), 7.10-7.16 (1H, m), 7.17-7.25 (2H, m), 7.32-7.37 (1H, m), 7.41-7.46(1H, m), 7.86 (1H, d, J=8.7, 2.7 Hz), 7.96 (1H, d, J=2.7 Hz), 8.46 (1H,s), 8.53 (1H, s).

Example 167

Production ofN-{3-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propyl}-2-(methylsulfonyl)acetamidehydrochloride (i) Production of tert-butyl[3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propyl]carbamate

The title compound (1.04 g) was obtained as a colorless oil by thereaction in the same manner as in Example 154 (i) using4-chloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg), tert-butyl3-bromopropylcarbamate (1.00 g), cesium carbonate (1.59 g) andN,N-dimethylacetamide (5.0 mL).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.02-2.12 (2H, m), 3.13-3.25 (2H, m),4.50-4.66 (3H, m), 6.78 (1H, d, J=3.0 Hz), 7.61-7.69 (1H, m), 8.71 (1H,s).

(ii) Production of tert-butyl{3-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propyl}carbamate

The title compound (398 mg) was obtained as a colorless amorphous solidby the reaction in the same manner as in Example 155 (ii) usingtert-butyl [3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propyl]carbamate(546 mg), 3-chloro-4-[3-(trifluoromethoxy)phenoxy]aniline (640 mg) andisopropyl alcohol (10 mL)

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 2.10-2.21 (2H, m), 3.17-3.27 (2H, m),4.40 (2H, t, J=7.5 Hz), 4.69-4.79 (1H, m), 6.62 (1H, d, J=3.0 Hz), 6.81(1H, br s), 6.85-6.95 (2H, m), 7.04-7.13 (2H, m), 7.29-7.34 (2H, m),7.54-7.60 (1H, m), 7.89 (1H, d, J=3.0 Hz), 8.52 (1H, s).

(iii) Production of5-(3-aminopropyl)-N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride

The title compound (355 mg) was obtained as colorless powder crystals bythe reaction in the same manner as in Example 155 (iii) using tert-butyl{3-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propyl}carbamate(398 mg), 2N hydrochloric acid (10 mL) and tetrahydrofuran (20 ml).

¹H-NMR (DMSO-d₆) δ: 2.03-2.16 (2H, m), 2.61-2.75 (2H, m), 4.86 (2H, t,J=6.6 Hz), 6.70 (1H, d, J=3.0 Hz), 6.94-7.01 (2H, m), 7.11-7.19 (1H, m),7.37 (1H, d, J=8.7 Hz), 7.52-7.58 (1H, m), 7.67 (1H, dd, J=8.7, 2.7 Hz),7.95 (1H, d, J=2.1 Hz), 7.96-815 (4H, m), 8.72 (1H, s), 9.96 (1H, br s).

(iv) Production ofN-{3-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propyl}-2-(methylsulfonyl)acetamidehydrochloride

N-{3-[4-({3-Chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propyl}-2-(methylsulfonyl)acetamidewas obtained by the reaction in the same manner as in Example 155 (iv)using5-(3-aminopropyl)-N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (170 mg), 2-(methylsulfonyl)acetic acid (85.0 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (177 mg),1-hydroxybenzotriazole monohydrate (141 mg), triethylamine (0.43 mL) andN,N-dimethylformamide (5.0 mL). To a solution ofN-{3-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propyl}-2-(methylsulfonyl)acetamidein ethyl acetate (1.0 mL) was added 4N hydrochloric acid-ethyl acetate(0.50 mL) at room temperature, and the mixture was stirred at roomtemperature for 1 hr. After concentration under reduced pressure,diisopropyl ether was added, and the precipitated crystals werecollected by filtration. The crystals were washed with diisopropyl etherto give the title compound (128 mg) as colorless powder crystals.

¹H-NMR (DMSO-d₆) δ: 1.88-2.00 (2H, m), 2.97-3.08 (2H, m), 3.11 (3H, s),4.04 (2H, s), 4.63-4.72 (2H, m), 6.67 (1H, d, J=3.0 Hz), 6.94-7.01 (2H,m), 7.13-7.21 (1H, m), 7.36 (1H, d, J=9.0 Hz), 7.49-7.65 (2H, m), 7.91(1H, d, J=2.4 Hz), 7.96 (1H, d, J=3.0 Hz), 8.45-8.52 (1H, m), 8.70 (1H,s), 9.67 (1H, br s).

Example 168

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-(methylsulfonyl)propanamide(i) Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-(methylthio)propanamide

To a mixture of5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (230 mg) and triethylamine (0.61 mL) in tetrahydrofuran(8.0 mL) was added 3-(methylthio)propionyl chloride (0.15 mL) underice-cooling. After stirring at room temperature for 20 hrs, water wasadded, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over magnesium sulfate andconcentrated under reduced pressure, and the residue was separated andpurified by basic silica gel column chromatography (eluent, ethylacetate→ethyl acetate:methanol=9:1) to give the title compound (133 mg)as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.13(3H, s), 2.59 (2H, t, J=6.9 Hz), 2.83 (2H, t,J=6.9 Hz), 3.57-3.69 (2H, m), 4.45-4.55 (2H, m), 6.39-6.47 (1H, m), 6.62(1H, d, J=3.0 Hz), 7.08 (1H, d, J=8.7 Hz), 7.09-7.14 (1H, m), 7.20 (1H,d, J=3.0 Hz), 7.23-7.27 (1H, m), 7.29-7.34 (1H, m), 7.39-7.47 (1H, m),7.83 (1H, dd, J=8.7, 2.7 Hz), 8.12 (1H, d, J=2.7 Hz), 8.523 (1H, s),8.63 (1H, s).

(ii) Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-(methylsulfonyl)propanamide

The title compound (97 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 165 usingN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-(methylthio)propanamide(150 mg), titanium tetraisopropoxide (40.3 μL), methanol (22.2 μL),water (9.3 μL), 70% aqueous tert-butyl hydroperoxide solution (0.12 mL)and dichloromethane (8.0 mL).

¹H-NMR (DMSO-d₆) δ: 2.41-2.57 (2H, m), 2.95 (3H, s), 3.26 (2H, t, J=7.5Hz), 3.35-3.45 (2H, m), 4.48-4.58 (2H, m), 6.51 (1H, d, J=3.0 Hz),7.18-7.32 (3H, m), 7.43-7.50 (1H, m), 7.58-7.67 (2H, m), 7.73-7.82 (1H,m), 8.02-8.07 (1H, m), 8.34-8.45 (2H, m), 8.75 (1H, s).

Example 169

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-methyl-2-(methylsulfonyl)propanamide

To a solution of 2-methyl-2-(methylsulfonyl)propanoic acid (115 mg) andN,N-dimethylformamide (catalytic amount) in tetrahydrofuran (5.0 mL) wasadded thionyl chloride (0.10 mL) at room temperature. After stirring atroom temperature for 3 hrs, the mixture was concentrated under reducedpressure. A solution of the residue in tetrahydrofuran (10 mL) was addeddropwise to a suspension of5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (180 mg) and triethylamine (0.48 mL) in tetrahydrofuran(10 mL) at room temperature. After stirring at room temperature for 20hrs, water was added to the reaction system and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over magnesium sulfate and concentrated underreduced pressure. The residue was separated and purified by basic silicagel column chromatography (eluent, ethyl acetate→ethylacetate:methanol=9:1) to give the title compound (205 mg) as colorlesscrystals.

¹H-NMR (CDCl₃) δ: 1.70 (6H, s), 2.93 (3H, s), 3.63-3.73 (2H, m),4.43-4.52 (2H, m), 6.64 (1H, d, J=3.3 Hz), 7.09 (1H, d, J=8.7 Hz),7.10-7.16 (1H, m), 7.18-7.24 (2H, m), 7.27-7.35 (2H, m), 7.40-7.47 (1H,m), 7.90 (1H, dd, J=8.7, 2.7 Hz), 8.05 (1H, d, J=2.7 Hz), 8.38 (1H, s),8.54 (1H, s)

melting point: 167-168° C.

Example 170

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-methyl-2-(methylsulfonyl)propanamide

To a solution of 2-methyl-2-(methylsulfonyl)propanoic acid (92 mg) andN,N-dimethylformamide (catalytic amount) in tetrahydrofuran (5.0 mL) wasadded thionyl chloride (80 μL) at room temperature. After stirring atroom temperature for 3 hrs, the mixture was concentrated under reducedpressure. A solution of the residue in tetrahydrofuran-dichloromethane(10 mL-10 mL) was added dropwise to a suspension of5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (150 mg) and triethylamine (0.39 mL) in tetrahydrofuran(10 mL) at room temperature. After stirring at room temperature for 20hrs, aqueous sodium hydrogen carbonate was added to the reaction systemand the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over magnesium sulfate andconcentrated under reduced pressure. The residue was separated andpurified by basic silica gel column chromatography (eluent, ethylacetate→ethyl acetate:methanol=9:1) to give the title compound (108 mg)as pale-yellow crystals.

¹H-NMR (CDCl₃) δ: 1.70 (6H, s), 2.93 (3H, s), 3.62-3.73 (2H, m)4.42-4.51 (2H, m), 6.64 (1H, d, J=3.3 Hz), 6.82-6.86 (1H, m), 6.88-6.96(2H, m), 7.09 (1H, d, J=9.0 Hz), 7.21 (1H, d, J=3.3 Hz), 7.26-7.35 (2H,m), 7.89 (1H, dd, J=9.0, 2.6 Hz), 8.04 (1H, d, J=2.6 Hz), 8.37 (1H, s),8.54 (1H, s).

Example 171

Production ofN-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-[2-(2-methoxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-aminehydrochloride

4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg) was dissolved inN,N-dimethylformamide (10 mL), and potassium carbonate (830 mg) and2-(2-methoxyethoxy)ethyl 4-methylbenzenesulfonate (920 mg) were addedand the mixture was stirred at room temperature for 12 hrs. Saturatedaqueous sodium hydrogen carbonate was added to the reaction mixtureunder ice-cooling, and the mixture was extracted with ethyl acetate. Theorganic layer was dried over magnesium sulfate and concentrated. Theresidue was purified by silica gel column chromatography (eluent,hexane:ethyl acetate=50:50→0:100). The obtained oil was dissolved inisopropyl alcohol (10 mL), and3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline was added. The mixturewas stirred at 90° C. for 4 hrs, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture under ice-cooling, and themixture was extracted with ethyl acetate. The extract was dried overmagnesium sulfate and concentrated. The residue was separated andpurified by silica gel column chromatography (eluent, ethylacetate:methanol=100:0→ethyl acetate:methanol=90:10), and crystallizedfrom 4N hydrochloric acid-ethyl acetate solution/hexane to give thetitle compound (277 mg).

¹H-NMR (DMSO-d₆) δ: 3.06 (3H, s), 3.33-3.35 (2H, m), 3.55-3.61 (2H, m),3.83-3.86 (2H, m), 4.83-4.86 (2H, m), 6.71 (1H, d, J=3 Hz), 7.24-7.72(7H, m), 7.99-8.04 (2H, m), 8.77 (1H, s), 9.92 (1H, s).

Example 172

Production ofN-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2-(methylsulfonyl)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production ofN-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2-(methylthio)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

The compound (150 mg) of Example 147 was dissolved in tetrahydrofuran(10 mL) and triethylamine (1.50 mL) and methanesulfonyl chloride (0.70mL) were added under ice-cooling, and the mixture was stirred for 1 hr.Saturated aqueous sodium hydrogen carbonate was added to this reactionsolution under ice-cooling, and the mixture was extracted with ethylacetate. The extract was dried over magnesium sulfate and concentrated,and the residue was dissolved in a mixed solvent ofN,N-dimethylformamide (5.0 mL) and tetrahydrofuran (4.0 mL). Sodiummethanethiolate (180 mg) was added, and the mixture was stirred at roomtemperature for 1 hr. Saturated aqueous sodium hydrogen carbonate wasadded to the reaction mixture under ice-cooling, and the mixture wasextracted with ethyl acetate. The extract was dried over magnesiumsulfate and concentrated. The residue was separated and purified bysilica gel column chromatography (eluent, ethylacetate:methanol=100:0→ethyl acetate:methanol=90:10) to give the titlecompound (123 mg).

¹H-NMR (CDCl₃) δ: 2.02 (3H, s), 2.66-2.73 (2H, m), 3.74-3.78 (2H, m),3.98-4.01 (2H, m), 4.55-4.58 (2H, m), 6.66 (1H, d, J=3 Hz), 7.07-7.63(6H, m), 7.88 (1H, br s), 8.02 (1H, s), 8.55 (1H, s), 8.74 (1H, s).

(ii) Production ofN-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2-(methylsulfonyl)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

N-{3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2-(methylthio)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(70.0 mg) was dissolved in dichloromethane (5.0 mL), titaniumtetraisopropoxide (0.10 mL), methanol (0.50 mL) and 70% aqueoustert-butyl hydroperoxide solution (8.0 mL) were added, and the mixturewas stirred at room temperature for 1 hr. Saturated aqueous sodiumthiosulfate solution was added to the reaction mixture underice-cooling, and the mixture was stirred at room temperature for 1 hrand extracted with dichloromethane. The extract was dried over magnesiumsulfate and concentrated, and the residue was separated and purified bysilica gel column chromatography (eluent, ethylacetate:methanol=100:0→ethyl acetate:methanol=90:10). Crystallizationfrom diethyl ether/ethyl acetate/hexane gave the title compound (62.5mg).

¹H-NMR (CDCl₃) δ: 2.62 (3H, s), 4.57-4.61 (2H, m), 6.68 (1H, d, J=3 Hz),4.16 (1H, m), 5.08 (2H, s), 5.55 (2H, s), 6.33 (1H, br s), 6.66 (1H, d,J=3 Hz), 7.09-7.60 (7H, m), 7.86 (1H, d, J=3 Hz), 8.11 (1H, s), 8.55(1H, s).

Example 173

Production ofN-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2-(2,2,2-trifluoroethoxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminehydrochloride

The title compound (107 mg) was obtained as crystals by the reaction inthe same manner as in Example 172 (i) using the compound (200 mg) ofExample 147, sodium 2,2,2-trifluoroethanolate (1.20 g), tetrahydrofuran(7.0 mL) and N,N-dimethylformamide (10 mL) at a reaction temperature of50° C., and crystallization from 4N hydrochloric acid-ethyl acetatesolution/hexane.

¹H-NMR (DMSO-d₆) δ: 3.09 (4H, m), 3.30-3.39 (2H, m), 4.61 (2H, br s),5.12 (2H, br s), 6.53 (1H, d, J=3 Hz), 7.20-8.56 (10H, m).

Example 174

Production of 2-(methylsulfonyl)ethyl{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate

5-(2-Aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (64.1 mg) and triethylamine (1.0 mL) were dissolved indichloromethane (5.0 mL),1-({[2-(methylsulfonyl)ethoxy]carbonyl}oxy)pyrrolidine-2,5-dione (45.6mg) was added, and the mixture was stirred at room temperature for 2hrs. Saturated aqueous sodium hydrogen carbonate was added to thereaction mixture under ice-cooling, and the mixture was extracted withethyl acetate. The extract was dried over magnesium sulfate andconcentrated, and the residue was separated and purified by silica gelcolumn chromatography (eluent, ethyl acetate:methanol=100:0→ethylacetate:methanol=95:5). Crystallization from diethyl ether/hexane gavethe title compound (61.0 mg).

¹H-NMR (CDCl₃) δ: 3.10 (3H, s), 3.48-3.52 (2H, m), 3.70-3.75 (2H, m),4.62-4.68 (2H, m), 4.75-4.79 (2H, m), 5.57 (1H, m), 6.78 (1H, d, J=3Hz), 7.22-7.61 (6H, m), 7.92 (1H, m), 8.11 (1H, m), 8.20 (1H, s), 8.68(1H, s).

Example 175

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-N′-[2-(methylsulfonyl)ethyl]urea

5-(2-Aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (54.1 mg) and triethylamine (0.7 mL) were dissolved indichloromethane (10 mL), 1,1′-carbonylbis(1H-imidazole) was added, andthe mixture was stirred at room temperature. After 1 hr,2-(methylsulfonyl)ethanamine (1.0 mL) was added, and the mixture wasfurther stirred for 1 hr. Saturated aqueous sodium hydrogen carbonatewas added to the reaction mixture under ice-cooling, and the mixture wasextracted with dichloromethane. The extract was dried over magnesiumsulfate and concentrated, and the residue was separated and purified bysilica gel column chromatography (eluent, ethylacetate:methanol=100:0→ethyl acetate:methanol=90:10). crystallized fromdiethyl ether/ethyl acetate/hexane to give the title compound (37.6 mg).

¹H-NMR (CDCl₃) δ: 2.84 (3H, s), 3.11-3.17 (2H, m), 3.40-3.50 (2H, m),3.66-3.72 (2H, m), 4.39-4.44 (2H, m), 5.55 (2H, m), 6.47 (1H, d, J=3Hz), 7.00-7.39 (6H, m), 7.81-7.88 (1H, m), 7.99 (1H, m), 8.40 (1H, s),8.73 (1H, s).

Example 176

Production of5-{2-[2-(tert-butylsulfonyl)ethoxy]ethyl}-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production of5-{2-[2-(tert-butylthio)ethoxy]ethyl}-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

2-{2-[4-({3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol(150 mg) was dissolved in tetrahydrofuran (6.0 mL), and triethylamine(1.00 mL) and methanesulfonyl chloride (0.59 mL) were added underice-cooling and the mixture was stirred for 1 hr. Saturated aqueoussodium hydrogen carbonate was added to this reaction solution underice-cooling and the mixture was extracted with ethyl acetate. Theextract was dried over magnesium sulfate and concentrated, and theresidue was dissolved in a mixed solvent of N,N-dimethylformamide (4.0mL) and tetrahydrofuran (6.0 mL). Sodium 2-methylpropane-2-thiolate (220mg) was added, and the mixture was stirred at room temperature for 1 hr.Saturated aqueous sodium hydrogen carbonate was added to the reactionmixture under ice-cooling and the mixture was extracted with ethylacetate. The extract was dried over magnesium sulfate and concentrated.The residue was separated and purified by silica gel columnchromatography (eluent, ethyl acetate:methanol=100:0→ethylacetate:methanol=90:10) to give the title compound (143 mg).

¹H-NMR (CDCl₃) δ: 1.23 (9H, s), 2.69-2.73 (2H, m), 3.73-3.78 (2H, m),3.97-3.99 (2H, m), 4.54-4.57 (2H, m), 6.66 (1H, d, J=3 Hz), 7.07-7.45(6H, m), 7.64-7.68 (1H, m), 7.89 (1H, d, J=3 Hz), 8.55 (1H, s), 8.77(1H, s).

(ii) Production of5-{2-[2-(tert-butylsulfonyl)ethoxy]ethyl}-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

5-{2-[2-(tert-Butylthio)ethoxy]ethyl}-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(140 mg) was dissolved in dichloromethane (5.0 mL), titaniumtetraisopropoxide (0.90 mL), methanol (0.20 mL) and 70% aqueoustert-butyl hydroperoxide solution (7.0 mL) were added, and the mixturewas stirred at room temperature for 1 hr. Saturated aqueous sodiumthiosulfate solution was added to the reaction mixture underice-cooling, and the mixture was stirred at room temperature for 1 hrand extracted with dichloromethane. The extract was dried over magnesiumsulfate and concentrated, and the residue was separated and purified bysilica gel column chromatography (eluent, ethylacetate:methanol=100:0→ethyl acetate:methanol=90:10). Crystallizationfrom diethyl ether/ethyl acetate/hexane gave the title compound (10.6mg).

¹H-NMR (CDCl₃) δ: 1.24 (9H, s), 3.00-3.04 (2H, m), 3.97-4.08 (4H, m),4.49-4.52 (2H, m), 6.59 (1H, d, J=3 Hz), 7.00-7.56 (7H, m), 7.84 (1H, d,J=3 Hz), 8.27 (1H, s), 8.48 (1H, s).

melting point: 79.5-81.5° C.

Example 177

Production ofN-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2-(phenylsulfonyl)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production ofN-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2-(phenylthio)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

The title compound (96.4 mg) was obtained by the reaction in the samemanner as in Example 172 (i) using the compound (100 mg) of Example 147,sodium benzenethiolate (200 mg), tetrahydrofuran (5.0 mL) andN,N-dimethylformamide (4.0 mL).

¹H-NMR (CDCl₃) δ: 3.06-3.10 (2H, m), 3.75-3.79 (2H, m), 3.94-3.97 (2H,m), 4.52-4.55 (2H, m), 6.66 (1H, d, J=3 Hz), 7.01-7.56 (12H, m), 7.88(1H, d, J=3 Hz), 8.56 (1H, s), 8.71 (1H, s).

(ii) Production ofN-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2-(phenylsulfonyl)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

The title compound (7.2 mg) was obtained by the reaction in the samemanner as in Example 172 (ii) usingN-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2-(phenylthio)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(60 mg), dichloromethane (5.0 mL), N,N-dimethylformamide (2.0 mL),titanium tetraisopropoxide (0.90 mL), methanol (0.20 mL) and 70% aqueoustert-butyl hydroperoxide solution (4.0 mL).

¹H-NMR (CDCl₃) δ: 3.23-3.27 (2H, m), 3.88-4.00 (4H, m), 4.42-4.45 (2H,m), 6.58 (1H, d, J=3 Hz), 7.00-7.70 (12H, m), 7.79 (1H, d, J=3 Hz), 8.13(1H, s), 8.47 (1H, s).

Example 178

Production of2-[(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)sulfinyl]ethanol

The compound (120 mg) obtained by the reaction in the same manner as inExample 172 (i) using the compound (200 mg) of Example 147, sodium2-hydroxyethanethiolate (2.02 g), tetrahydrofuran (6.0 mL) andN,N-dimethylformamide (5.0 mL) was dissolved in dichloromethane (7.0mL). m-Chloroperbenzoic acid (110 mg) was added at −18° C. and themixture was stirred for 5 hrs. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture under ice-cooling, and themixture was extracted with dichloromethane. The extract was dried overmagnesium sulfate and concentrated, and the residue was separated andpurified by silica gel column chromatography (eluent, ethylacetate:methanol=100:0→ethyl acetate:methanol=80:20). Crystallizationfrom diethyl ether/ethyl acetate/hexane gave the title compound (97.0mg).

¹H-NMR (CDCl₃) δ: 2.66-2.73 (2H, m), 2.90-2.98 (2H, m), 3.93-4.13 (6H,m), 4.56-4.62 (2H, m), 6.68 (1H, d, J=3 Hz), 7.08-7.59 (7H, m), 7.83(1H, d, J=3 Hz), 8.37 (1H, m), 8.55 (1H, s).

Example 179

Production of2-[(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)sulfonyl]ethanol

The title compound (60.2 mg) was obtained as crystals by the reaction inthe same manner as in Example 172 (ii) using the compound (87.0 mg) ofExample 178, dichloromethane (4.0 mL), N,N-dimethylformamide (2.0 mL),titanium tetraisopropoxide (0.90 mL), methanol (0.50 mL) and 70% aqueoustert-butyl hydroperoxide solution (5.0 mL).

¹H-NMR (CDCl₃) δ: 2.78-2.82 (2H, m), 3.34-3.38 (2H, m), 3.79 (2H, m),4.03-4.13 (4H, m), 4.57-4.60 (2H, m), 6.68 (1H, d, J=3 Hz), 7.07-7.57(7H, m), 7.80 (1H, d, J=3 Hz), 8.23 (1H, m), 8.54 (1H, s).

Example 180

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-1-(methylsulfonyl)methanesulfonamide

5-(2-Aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (245 mg) and N-methylmorpholine (1.0 mL) were dissolvedin dichloromethane (6.0 mL), (methylsulfonyl)methanesulfonyl chloride(0.40 mL) was added dropwise under ice-cooling, and the mixture wasstirred for 1 hr. Saturated aqueous sodium hydrogen carbonate was addedunder ice-cooling, and the mixture was extracted with dichloromethane.The extract was dried over magnesium sulfate and concentrated, and theresidue was separated and purified by silica gel column chromatography(eluent, ethyl acetate:methanol=100:0→ethyl acetate:methanol=80:20).Crystallization from diethyl ether/ethyl acetate to give the titlecompound (79.4 mg) as crystals.

¹H-NMR (CDCl₃) δ: 3.60 (3H, br s), 3.83-3.92 (4H, m), 4.82 (2H, br s),6.68 (1H, d, J=3 Hz), 7.24-7.99 (8H, m), 8.73 (1H, s), 8.73 (1H, s),9.72 (1H, s).

Example 181

Production of3-[2-chloro-4-(6,7-dihydro-9H-pyrimido[4′,5′:4,5]pyrrolo[2,1-c][1,4]oxazin-4-ylamino)phenoxy]benzonitrilehydrochloride (i) Production of4-phenoxy-6,7-dihydro-9H-pyrimido[4′,5′:4,5]pyrrolo[2,1-c][1,4]oxazine

The compound (130 mg) obtained in Example 21 (ii) was dissolved inN,N-dimethylformamide (2.16 mL), and cesium carbonate (1.05 g) and1,2-dibromoethane (0.255 mL) were sequentially added. The mixture wasstirred at room temperature for 16 hrs. The reaction mixture was dilutedwith ethyl acetate (30 mL), and washed with water (20 mL). The organiclayer was separated, dried over magnesium sulfate and concentrated underreduced pressure. The residue was dissolved in N,N-dimethylformamide(1.08 mL), potassium t-butoxide (90.5 mg) was added, and the mixture wasstirred at room temperature for 1 hr. Ethyl acetate (30 mL)/water (20mL) was added, and the organic layer was dried over magnesium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=70/30→0/100) togive the title compound (76 mg).

¹H-NMR (CDCl₃) δ 4.20 (2H, t, J=5 Hz), 4.55 (2H, t, J=5 Hz), 5.06 (2H,s), 6.40 (1H, s), 7.2-7.5 (5H, m), 8.44 (1H, s).

(ii) Production of3-[2-chloro-4-(6,7-dihydro-9H-pyrimido[4′,5′:4,5]pyrrolo[2,1-c][1,4]oxazin-4-ylamino)phenoxy]benzonitrilehydrochloride

A mixture of4-phenoxy-6,7-dihydro-9H-pyrimido[4′,5′:4,5]pyrrolo[2,1-c][1,4]oxazine(69 mg), 3-(4-amino-2-chlorophenoxy)benzonitrile (95 mg), pyridinehydrochloride (75 mg) and 1-methyl-2-pyrrolidone (1 mL) was stirred at140° C. for 14 hrs. After the completion of the reaction, the mixturewas diluted with ethyl acetate and washed with saturated aqueous sodiumhydrogen carbonate and saturated brine. The organic layer was dried overmagnesium sulfate. After concentration under reduced pressure, theresidue was subjected to silica gel column chromatography (hexane/ethylacetate=50/50→0/100). The obtained fractions were collected andconcentrated, and the residue was dissolved in ethyl acetate (2 mL) andtreated with 4N hydrochloric acid/ethyl acetate (0.13 mL) to give thetitle compound (81 mg) as hydrochloride crystals.

¹H-NMR (DMSO-d₆) δ 4.17 (2H, t, J=5 Hz), 4.75 (2H, m), 5.07 (2H, s),6.55 (1H, s), 7.2-7.7 (6H, m), 7.94 (1H, m), 8.70 (1H, s), 9.91 (1H, brs).

Example 182

Production ofN-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-(2-{[2-(methylsulfonyl)ethyl]amino}ethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(i) Production of4-chloro-5-(2,2-diethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine

4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (1 g) was dissolved inN,N-dimethylformamide (13 mL), cesium carbonate (6.37 g) and2-bromo-1,1-diethoxyethane (2.94 mL) were sequentially added and themixture was stirred at 80° C. for 4.5 hrs. The reaction mixture wasdiluted with ethyl acetate (100 mL), and washed with water (80 mL). Theorganic layer was separated, dried over magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=50/50→0/100) to give the titlecompound (1.26 g) as a yellow oil.

¹H-NMR (CDCl₃) δ 1.14 (6H, t, J=6 Hz), 3.40 (2H, m), 3.72 (2H, m), 4.08(1H, m), 4.56 (2H, d, J=5 Hz), 6.71 (1H, d, J=3 Hz), 7.55 (1H, d, J=3Hz), 8.69 (1H, s).

(ii) Production of4-phenoxy-5-(2,2-diethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine

A mixture of 4-chloro-5-(2,2-diethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine(1 g), phenol (420 mg), potassium carbonate (617 mg) and1-methyl-2-pyrrolidone (6.74 mL) was stirred with heating at 140° C. for6 hrs. The reaction mixture was diluted with ethyl acetate (100 mL), andwashed with water (80 mL). The organic layer was separated, dried overmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=90/10→40/60) to give the title compound (1.15 g) as a yellowoil.

¹H-NMR (CDCl₃) δ 1.13 (6H, t, J=7 Hz), 3.40 (2H, m), 3.69 (2H, m), 4.51(2H, d, J=6 Hz), 4.76 (1H, t, J=6 Hz), 6.65 (1H, d, J=3 Hz), 7.2-7.5(6H, m), 8.45 (1H, s).

(iii) Production of2-(4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethane-1,1-diol

4-Phenoxy-5-(2,2-diethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine (1.1 g) wasdissolved in dichloromethane (4.53 mL)/trifluoroacetic acid (4.53 mL),and the mixture was stirred at room temperature for 16 hrs. The reactionmixture was concentrated under reduced pressure, and the residue wasdissolved in ethyl acetate (100 mL). The mixture was washed withsaturated aqueous sodium hydrogen carbonate (80 mL), and the organiclayer was dried over magnesium sulfate and concentrated under reducedpressure to give the title compound (826 mg) as a white solid.

¹H-NMR (DMSO-d₆) δ 4.35 (2H, d, J=6 Hz), 5.17 (1H, t, J=6 Hz), 6.14 (2H,d, J=6 Hz), 6.59 (1H, d, J=3 Hz), 7.2-7.6 (5H, m), 7.75 (1H, d, J=3 Hz),8.28 (1H, s).

(iv) Production of2-(methylsulfonyl)-N-[2-(4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]ethanamine

2-(4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethane-1,1-diol (500 mg)and 2-(methylsulfonyl)ethylamine (341 mg) were dissolved inN,N-dimethylformamide (29 mL)/acetic acid (2.9 mL), and the mixture wasstirred at room temperature for 1.5 hrs. Sodium triacetoxyborohydride(579 mg) was added, and the mixture was stirred at room temperature for16 hrs. The reaction mixture was concentrated under reduced pressure,and the residue was purified by silica gel column chromatography (ethylacetate/methanol=100/0→70/30) to give the title compound (508 mg) as acandy-like substance.

¹H-NMR (CDCl₃) δ 2.84 (3H, s), 3.0-3.2 (6H, m), 4.54 (2H, t, J=6 Hz),6.66 (1H, d, J=3 Hz), 7.2-7.5 (6H, m), 8.45 (1H, s).

(v) Production ofN-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-(2-{[2-(methylsulfonyl)ethyl]amino}ethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

2-(Methylsulfonyl)-N-[2-(4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]ethanamine(500 mg) was dissolved in tetrahydrofuran (5 mL), and di-tert-butyldicarbonate (0.478 mL) and triethylamine (0.29 mL) were added, and themixture was stirred at room temperature for 3 hrs. The reaction mixturewas concentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (hexane/ethyl acetate=80/20→0/100). Amixture of a portion (243 mg) taken from the obtained residue (491 mg),3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (228 mg), pyridinehydrochloride (183 mg) and phenol (406 mg) was stirred at 140° C. for 14hrs. After the completion of the reaction, the mixture was diluted withdichloromethane (50 mL) and washed with saturated aqueous sodiumhydrogen carbonate (30 mL). The organic layer was dried over magnesiumsulfate. After concentration under reduced pressure, the residue wassubjected to silica gel column chromatography (ethylacetate/methanol=100/0→70/30) and crystallized from diisopropyl ether togive the title compound (123 mg).

¹H-NMR (DMSO-d₆) δ 2.88 (3H, s), 2.89 (2H, m), 2.99 (2H, m), 3.16 (2H,t, J=6 Hz), 4.50 (2H, m), 6.51 (1H, d, J=3 Hz), 7.22 (2H, m), 7.31 (1H,d, J=9 Hz), 7.46 (1H, d, J=8 Hz), 7.5-7.7 (3H, m), 8.04 (1H, d, J=2 Hz),8.35 (1H, s).

Example 183

Production of2-[2-(4-{[4-[(6-methylpyridin-3-yl)oxy]-3-(trifluoromethyl)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethanol

A mixture of 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethylbenzoate (150 mg),4-[(6-methylpyridin-3-yl)oxy]-3-(trifluoromethyl)aniline (175 mg) and1-methyl-2-pyrrolidone (0.863 mL) was stirred with heating at 140° C.for 2.5 hrs. The reaction mixture was diluted with ethyl acetate (80 mL)and washed with aqueous sodium hydrogen carbonate (30 mL). The organiclayer was separated, dried over magnesium sulfate and evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/methanol=100/0→90/10). The object fractionwas concentrated under reduced pressure. The obtained residue wasdissolved in methanol (1.9 mL), 1N sodium hydroxide (0.433 mL) wasadded, and the mixture was stirred at room temperature for 1.5 hrs. 1Nhydrochloric acid (0.433 mL) was added, and the mixture was diluted withethyl acetate (80 mL) and washed with saturated brine (30 mL). Theorganic layer was dried over magnesium sulfate. After concentrationunder reduced pressure, the residue was subjected to silica gel columnchromatography (ethyl acetate/methanol=100/0→90/10) and crystallizedfrom diisopropyl ether to give the title compound (118 mg).

¹H-NMR (DMSO-d₆) δ 2.46 (3H, s), 3.47 (4H, br s), 3.82 (2H, m), 4.66(3H, m), 6.51 (1H, d, J=3 Hz), 7.10 (1H, d, J=9 Hz), 7.31 (2H, m), 7.68(1H, d, J=3 Hz), 7.90 (1H, dd, J=3 Hz, 9 Hz), 8.10 (1H, d, J=3 Hz), 8.24(1H, d, J=3 Hz), 8.30 (1H, s), 8.99 (1H, br s).

Example 184

Production of2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethanol

The title compound (81 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 183 using2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl benzoate (100 mg),3-chloro-4-(3-chlorophenoxy)aniline (126 mg) and 1-methyl-2-pyrrolidone(0.66 mL).

¹H-NMR (DMSO-d₆) δ 3.87 (2H, m), 4.53 (2H, t, J=4.5 Hz), 6.31 (1H, brs), 6.51 (1H, d, J=3 Hz), 6.88 (1H, d, J=9 Hz), 6.95 (1H, s), 7.15 (1H,d, J=9 Hz), 7.28 (1H, d, J=9 Hz), 7.38 (1H, t, J=9 Hz), 7.60 (1H, dd,J=2 Hz, 9 Hz), 7.66 (1H, d, J=3 Hz), 7.97 (1H, d, J=2 Hz), 8.34 (1H, s),9.89 (1H, br s).

Example 185

Production of2-{2-[4-({3-methoxy-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol

The title compound (80 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 183 using2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate(150 mg), 3-methoxy-4-[3-(trifluoromethyl)phenoxy]aniline (185 mg) and1-methyl-2-pyrrolidone (0.863 mL).

¹H-NMR (DMSO-d₆) δ 3.52 (4H, m), 3.74 (3H, s), 3.85 (2H, t, J=5 Hz),4.65 (2H, t, J=5 Hz), 4.76 (1H, t, J=5 Hz), 6.51 (1H, d, J=3 Hz), 7.13(3H, m), 7.35 (2H, m), 7.49 (1H, d, J=2 Hz), 7.55 (1H, t, J=8 Hz), 7.68(1H, d, J=3 Hz), 8.32 (1H, s), 8.90 (1H, br s).

Example 186

Production of2-{2-[4-({3-(hydroxymethyl)-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol

The title compound (175 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 183 using2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate(150 mg), {5-amino-2-[3-(trifluoromethyl)phenoxy]phenyl}methanol (184mg) and 1-methyl-2-pyrrolidone (0.863 mL).

¹H-NMR (DMSO-d₆) δ 3.52 (4H, m), 3.74 (3H, s), 3.85 (2H, t, J=5 Hz),4.65 (2H, t, J=5 Hz), 4.76 (1H, t, J=5 Hz), 6.51 (1H, d, J=3 Hz), 7.13(3H, m), 7.35 (2H, m), 7.49 (1H, d, J=2 Hz), 7.55 (1H, t, J=8 Hz), 7.68(1H, d, J=3 Hz), 8.32 (1H, s), 8.90 (1H, br s).

Example 187

Production of2-{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol

The title compound (98 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 183 using2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate(150 mg), 3-methyl-4-[3-(trifluoromethyl)phenoxy]aniline (174 mg) and1-methyl-2-pyrrolidone (0.863 mL).

¹H-NMR (DMSO-d₆) δ 2.13 (3H, s), 3.51 (4H, m), 3.84 (2H, t, J=4.5 Hz),4.63 (2H, t, J=4.5 Hz), 4.74 (1H, t, J=4.5 Hz), 6.49 (1H, d, J=3 Hz),7.04 (1H, d, J=9 Hz), 7.16 (2H, m), 7.41 (1H, d, J=8 Hz), 7.5-7.7 (4H,m), 8.29 (1H, s), 8.83 (1H, br s).

Example 188

Production of2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}acetamide(i) Production of tert-butyl{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate

A mixture of tert-butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (297 mg),3-methyl-4-[3-(trifluoromethyl)phenoxy]aniline (401 mg) and isopropylalcohol (2.97 mL) was stirred at 80° C. for 16 hrs. The reaction mixturewas diluted with ethyl acetate (80 mL), and washed with aqueous sodiumhydrogen carbonate (30 mL). The organic layer was separated, dried overmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=90/10→0/100) to give the title compound (528 mg) as a whitepowder.

¹H-NMR (CDCl₃) δ 1.47 (9H, s), 2.21 (3H, s), 3.50 (2H, m), 4.46 (2H, m),5.11 (1H, m), 6.58 (1H, d, J=3 Hz), 6.97 (1H, d, J=9 Hz), 7.0-7.2 (3H,m), 7.27 (1H, m), 7.39 (1H, t, J=8 Hz), 7.69 (2H, m), 8.45 (1H, br s),8.50 (1H, s).

(ii) Production of5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

tert-Butyl{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate(494 mg) was dissolved in dichloromethane (6.4 mL), trifluoroacetic acid(4.8 mL) was added, and the mixture was stirred at room temperature for1 hr. The reaction mixture was concentrated under reduced pressure, andthe residue was diluted with ethyl acetate (50 mL), and washed withaqueous sodium hydrogen carbonate (30 mL). The organic layer wasseparated, dried over magnesium sulfate and concentrated under reducedpressure to give the title compound (442 mg) as a powder.

¹H-NMR (CDCl₃) δ 2.20 (3H, s), 3.30 (2H, t, J=5 Hz), 4.46 (2H, t, J=5Hz), 6.61 (1H, d, J=3 Hz), 6.95 (1H, d, J=9 Hz), 7.0-7.5 (6H, m), 7.51(1H, d, J=3 Hz), 8.50 (1H, s).

(iii) Production of2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}acetamide

The title compound (89 mg) was obtained as colorless powder crystals bythe reaction in the same manner as in Example 155 (iv) using5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(196 mg), 2-(methylsulfonyl)acetic acid (64 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (133 mg),1-hydroxybenzotriazole monohydrate (94 mg), triethylamine (0.319 mL) andN,N-dimethylformamide (5.0 mL).

¹H-NMR (DMSO-d₆) δ 2.14 (3H, s), 3.09 (3H, s), 3.45 (2H, m)), 4.05 (2H,s), 4.56 (2H, t, J=7 Hz), 6.47 (1H, d, J=3 Hz), 7.04 (1H, d, J=9 Hz),7.17 (2H, m), 7.47 (1H, m), 7.59 (4H, m), 8.29 (1H, s), 8.55 (1H, br s),8.67 (1H, t, J=5.5 Hz).

Example 189

Production of2-{2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol

The title compound (128 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 183 using2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate(150 mg), 3-methyl-4-[3-(trifluoromethoxy)phenoxy]aniline (184 mg) and1-methyl-2-pyrrolidone (0.863 mL).

¹H-NMR (DMSO-d₆) δ 2.12 (3H, s), 3.51 (4H, m), 3.84 (2H, t, J=5 Hz),4.63 (2H, t, J=5 Hz), 4.73 (1H, t, J=5 Hz), 6.49 (1H, d, J=3 Hz), 6.87(2H, m), 7.04 (2H, m), 7.47 (1H, t, J=8 Hz), 7.59 (2H, m), 7.66 (1H, d,J=3 Hz), 8.29 (1H, s), 8.82 (1H, br s).

Example 190

Production of2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}acetamide(i) Production of tert-butyl{2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate

tert-Butyl [2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate(297 mg) and 3-methyl-4-[3-(trifluoromethoxy)phenoxy]aniline (425 mg)were dissolved in isopropyl alcohol (2.97 mL), and the mixture wasstirred at 80° C. for 16 hrs. After cooling to room temperature, themixture was diluted with ethyl acetate (60 mL), and washed with aqueoussodium hydrogen carbonate (30 mL). The organic layer was dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography (eluent, hexane:ethylacetate=80:20→0:100) to give the title compound (563 mg) as a whitepowder.

¹H-NMR (CDCl₃) δ 1.47 (9H, s), 2.20 (3H, s), 3.49 (2H, m), 4.46 (2H, m),5.08 (1H, m), 6.59 (1H, d, J=3 Hz), 6.78 (1H, m), 6.86 (2H, m), 6.97(1H, m), 7.16 (1H, d, J=3 Hz), 7.27 (2H, m), 7.69 (2H, m), 8.43 (1H, brs), 8.50 (1H, s).

(ii) Production of5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

tert-Butyl{2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate(523 mg) was dissolved in dichloromethane (6.4 mL), trifluoroacetic acid(4.8 mL) was added, and the mixture was stirred at room temperature for2 hrs. The reaction mixture was concentrated under reduced pressure, andthe residue was diluted with ethyl acetate (50 mL), and washed withaqueous sodium hydrogen carbonate (40 mL). The organic layer wasseparated, dried over magnesium sulfate and concentrated under reducedpressure to give the title compound (420 mg) as a white powder.

¹H-NMR (CDCl₃) δ 2.20 (3H, s), 3.30 (2H, t, J=4.5 Hz), 4.46 (2H, t,J=4.5 Hz), 6.62 (1H, d, J=3 Hz), 6.85 (3H, m), 6.96 (1H, d, J=9 Hz),7.19 (1H, d, J=3 Hz), 7.27 (1H, m), 7.44 (1H, dd, J=2 Hz, 9 Hz), 7.50(1H, d, J=3 Hz), 8.50 (1H, s).

(iii) Production of2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}acetamide

A solution of5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(174 mg), 2-(methylsulfonyl)acetic acid (54 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (112 mg),1-hydroxybenzotriazole monohydrate (79 mg) and triethylamine (0.273 mL)in N,N-dimethylformamide (7.69 mL) was stirred at room temperature for16 hrs. The reaction mixture was diluted with ethyl acetate (80 mL), andwashed with water (60 mL). The organic layer was dried over magnesiumsulfate and concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography (eluent, ethylacetate:methanol=100:0→92:8), and crystallized from diisopropyl ether togive the title compound (92 mg) as colorless crystals.

¹H-NMR (DMSO-d₆) δ 2.14 (3H, s), 3.10 (3H, s), 3.46 (2H, q, J=6 Hz),4.06 (2H, s), 4.56 (2H, t, J=6 Hz), 6.48 (1H, d, J=3 Hz), 6.89 (2H, m),7.06 (2H, m), 7.48 (1H, t, J=8 Hz), 7.59 (3H, m), 8.30 (1H, s), 8.55(1H, br s), 8.67 (1H, t, J=6 Hz).

melting point: 106-108° C.

Example 191

Production ofN-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-2-(methylsulfonyl)acetamide(i) Production of tert-butyl2-(4-([3-chloro-4-(3-chlorophenoxy)phenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethylcarbamate

A mixture of tert-butyl2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethylcarbamate (1.19 g),3-chloro-4-(3-chlorophenoxy)aniline (1.22 g) and isopropyl alcohol (12.0mL) was stirred at 80° C. for 15 hrs. Under ice-cooling, aqueous sodiumhydrogen carbonate was added, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overanhydrous magnesium sulfate. The solvent was concentrated under reducedpressure, and the residue was purified by silica gel chromatography(eluent:hexane/ethyl acetate=50/50→100/0), and washed with diisopropylether-hexane to give the title compound (1.69 g) as crystals.

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 3.4-3.6 (2H, m), 4.4-4.6 (2H, m),5.0-5.1 (1H, m), 6.61 (1H, d, J=2.6 Hz), 6.85-7.05 (2H, m), 7.07 (2H, d,J=8.8 Hz), 7.18 (1H, d, J=2.6 Hz), 7.2-7.3 (1H, m), 7.85-7.95 (1H, m),8.0-8.05 (1H, m), 8.52 (1H, s), 8.62 (1H, br s).

(ii) Production of5-(2-aminoethyl)-N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride

To a solution of tert-butyl2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethylcarbamate(1.69 g) in tetrahydrofuran (32 mL) was added 2N hydrochloric acid (16mL). The reaction mixture was stirred at 65° C. for 18 hrs andconcentrated. Ethanol was added, and the mixture was concentrated again.Ethyl acetate and diisopropyl ether were added to the residue, and theprecipitate was collected by filtration and washed with diisopropylether to give the title compound (1.50 g) as crystals.

¹H-NMR (DMSO-d₆+CDCl₃) δ: 3.3-3.6 (4H, m), 5.0-5.15 (2H, m), 6.71 (1H,d, J=3.2 Hz), 6.9-7.0 (2H, m), 7.1-7.2 (1H, m), 7.22 (1H, d, J=8.8 Hz),7.3-7.45 (1H, m), 7.6-7.7 (1H, m), 7.87 (1H, d, J=2.6 Hz), 8.05 (1H, d,J=2.4 Hz), 8.2-8.4 (2H, m), 8.71 (1H, s).

(iii) Production ofN-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-2-(methylsulfonyl)acetamide

To a solution of5-(2-aminoethyl)-N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (200 mg), 2-(methylsulfonyl)acetic acid (113 mg) and1-hydroxybenzotriazole (122 mg) in N,N-dimethylformamide (5.0 mL) wereadded a solution of triethylamine (419 mg) in N,N-dimethylformamide(1.25 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (173 mg) under ice-cooling. After stirring the reactionmixture at room temperature for 16 hrs, water was added underice-cooling, and the mixture was extracted twice with ethyl acetate. Theorganic layers were collected, dried over anhydrous magnesium sulfateand concentrated. The residue was purified by silica gel columnchromatography (eluent:ethyl acetate/methanol=100/0→80/20), andrecrystallized from ethanol-ethyl acetate-diisopropyl ether to give thetitle compound (151 mg) as crystals.

¹H-NMR (CDCl₃) δ: 3.13 (3H, s), 3.6-3.8 (2H, m), 3.99 (2H, s), 4.4-4.6(2H, m), 6.62 (1H, d, J=3.4 Hz), 6.85-6.95 (2H, m), 7.0-7.1 (2H, m),7.2-7.3 (2H, m), 7.7-7.8 (1H, m), 7.95-8.0 (1H, m), 8.19 (1H, s), 8.52(1H, s).

melting point: 206-207° C.

Example 192

Production of2-[{3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propyl}(methyl)amino]ethanoldihydrochloride (i) Production of4-chloro-5-(3-chloropropyl)-5H-pyrrolo[3,2-d]pyrimidine

To a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.54 g) inN,N-dimethylformamide (20 mL) was added cesium carbonate (4.89 g) underice-cooling, and the mixture was stirred under ice-cooling for 20 min.1-Bromo-3-chloropropane (1.89 g) was added and the mixture was stirredunder ice-cooling for 1 hr and at room temperature for 32 hrs. Thereaction mixture was poured into water (40 mL), and the mixture wasextracted with ethyl acetate (60 mL×2). The organic layers werecombined, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent, hexane:ethyl acetate=80:20→50:50) to give thetitle compound (1.87 g).

¹H-NMR (CDCl₃) δ: 2.35 (2H, m), 3.49 (2H, t, J=6.0 Hz), 4.69 (2H, t,J=6.6 Hz), 6.73 (1H, d, J=3.0 Hz), 7.56 (1H, d, J=3.0 Hz), 8.70 (1H, s).

(ii) Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(3-chloropropyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

A mixture of 4-chloro-5-(3-chloropropyl)-5H-pyrrolo[3,2-d]pyrimidine(839 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (1.10 g) and isopropylalcohol (5 mL) was stirred at 80° C. for 1.5 hrs. The mixture wasconcentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate (30 mL) was added to the residue, and the mixture wasextracted with ethyl acetate (30 mL×3). The organic layers werecombined, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent, hexane:ethyl acetate=90:10-20:80) to give thetitle compound (1.19 g).

¹H-NMR (CDCl₃) δ: 2.36 (2H, m), 3.56 (2H, t, J=5.7 Hz), 4.47 (2H, t,J=6.9 Hz), 5.14 (2H, s), 6.60 (1H, d, J=3.3 Hz), 6.73 (1H, br s), 6.94(1H, d, J=8.7 Hz), 7.02 (1H, m), 7.19-7.40 (5H, m), 7.65 (1H, d, J=3.3Hz), 8.49 (1H, s).

(iii) Production of2-[{3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propyl}(methyl)amino]ethanoldihydrochloride

A mixture ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(3-chloropropyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(634 mg), 2-methylaminoethanol (534 mg) and N,N-dimethylformamide (5 mL)was stirred at room temperature for 64 hrs. After concentration underreduced pressure, saturated aqueous sodium hydrogen carbonate (10 mL)was added to the residue, and the mixture was extracted with ethylacetate (55 mL×2). The organic layer was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by basic silica gel column chromatography (eluent, hexane:ethylacetate=80:20→0:100). 4N Hydrogen chloride-ethyl acetate solution (10mL) was added to the obtained amorphous solid and, after concentrationunder reduced pressure, the residue was recrystallized fromethanol-ethyl acetate to give the title compound (523 mg).

¹H-NMR (DMSO-d₆) δ: 2.16-2.32 (2H, m), 2.74 (3H, s), 2.94-3.40 (4H, m),3.62-3.80 (2H, m), 4.74-4.84 (2H, m), 5.31 (2H, s), 6.69 (1H, m), 7.20(1H, m), 7.29-7.36 (5H, m), 7.43-7.50 (2H, m), 7.71 (1H, m), 8.03 (1H,br s), 8.64 (1H, s), 9.84 (1H, br s), 10.12 (1H, br s).

Example 193

Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-[3-(dimethylamino)propyl]-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride

N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(3-chloropropyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(560 mg) was dissolved in 2.0 M dimethylamine-tetrahydrofuran solution(5 mL), and the mixture was stirred at room temperature for 26 hrs. A2.0 M dimethylamine-tetrahydrofuran solution (5 mL) was further addedand the mixture was stirred at room temperature for 20 hrs. A 2.0 Mdimethylamine-tetrahydrofuran solution (10 mL) was further added, andthe mixture was stirred at room temperature for 24 hrs. Afterconcentration of the reaction mixture under reduced pressure, saturatedaqueous sodium hydrogen carbonate (20 mL) was added to the residue, andthe mixture was extracted with ethyl acetate (35 mL×2). The organiclayer was dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by basic silica gel columnchromatography (eluent, hexane:ethyl acetate=90:10→20:80), and 4Nhydrogen chloride-ethyl acetate solution (10 mL) was added to theobtained amorphous solid. After concentration under reduced pressure,the residue was recrystallized from ethanol-ethyl acetate to give thetitle compound (428 mg).

¹H-NMR (DMSO-d₆) δ: 2.18-2.26 (2H, m), 2.70 (6H, s), 2.94-3.04 (2H, m),4.77-4.84 (2H, m), 5.30 (2H, s), 6.67 (1H, m), 7.19 (1H, m), 7.28-7.34(4H, m), 7.43-7.51 (2H, m), 7.71 (1H, m), 8.04 (1H, m), 8.63 (1H, s),9.87 (1H, br s), 10.74 (1H, br s).

Example 194

Production of6-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6,7,8,9-tetrahydro-3,5,6,9a-tetraazabenzo[cd]azulene

A mixture ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(3-chloropropyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(839 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (1.10 g) and1-methyl-2-pyrrolidone (5 mL) was stirred at 140° C. for 1 hr. Thereaction mixture was poured into water (10 mL) and adjusted to pH 8 withsaturated aqueous sodium hydrogen carbonate. The mixture was extractedwith ethyl acetate (40 mL×3), and the organic layers were combined anddried over anhydrous magnesium sulfate. After concentration underreduced pressure, the residue was subjected to silica gel columnchromatography (eluent, hexane:ethyl acetate=60:40→50:50) and furthersubjected to basic silica gel column chromatography (eluent,hexane:ethyl acetate=80:20→0:100). The object fraction was concentratedunder reduced pressure. Chloroform-diisopropyl ether was added to theresidue, and the solid was collected by filtration and dried.Recrystallization from ethyl acetate gave the title compound (74.5 mg).

¹H-NMR (DMSO-d₆) δ: 2.31 (2H, m), 3.88 (2H, m), 4.31 (2H, m), 5.27 (2H,s), 6.47 (1H, d, J=3.0 Hz), 7.14-7.36 (5H, m), 7.42 (1H, d, J=2.4 Hz),7.47 (1H, m), 7.65 (1H, d, J=3.0 Hz), 8.02 (1H, s).

Example 195

Production of6-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-6,7,8,9-tetrahydro-3,5,6,9a-tetraazabenzo[cd]azulene(i) Production of5-(3-chloropropyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine

A mixture of 4-chloro-5-(3-chloropropyl)-5H-pyrrolo[3,2-d]pyrimidine(789 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (1.09 g) andisopropyl alcohol (5 mL) was stirred at 80° C. for 4.5 hrs. The mixturewas concentrated under reduced pressure, saturated aqueous sodiumhydrogen carbonate (30 mL) was added to the residue, and the mixture wasextracted with ethyl acetate (40 mL×3). The organic layers werecombined, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent, hexane:ethyl acetate=90:10→20:80) to give thetitle compound (1.46 g).

¹H-NMR (CDCl₃) δ: 2.39 (2H, m), 3.60 (2H, t, J=5.6 Hz), 4.53 (2H, t,J=6.9 Hz), 6.62 (1H, d, J=3.3 Hz), 6.96 (1H, br s), 7.07 (1H, d, J=8.7Hz), 7.08-7.49 (6H, m), 7.87 (1H, m), 8.55 (1H, s).

(ii) Production of6-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-6,7,8,9-tetrahydro-3,5,6,9a-tetraazabenzo[cd]azulene

A mixture of5-(3-chloropropyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(470 mg), potassium carbonate (270 mg) and ethylene glycol (10 mL) wasstirred at room temperature for 18.5 hrs, and at 60° C. for 4 hrs. Thereaction mixture was poured into aqueous sodium hydrogen carbonate (20mL), and the mixture was extracted with ethyl acetate (50 mL×2). Theorganic layers were combined, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent, hexane:ethyl acetate=90:10→0:100),and the obtained solid was recrystallized from ethanol-water to give thetitle compound (116 mg).

¹H-NMR (DMSO-d₆) δ: 2.45 (2H, m), 3.99 (2H, t, J=4.8 Hz), 4.34 (2H, t,J=5.4 Hz), 6.65 (1H, d, J=3.0 Hz), 7.06 (1H, d, J=9.0 Hz), 7.16-7.22(2H, m), 7.28 (1H, m), 7.33 (1H, d, J=3.0 Hz), 7.37 (1H, m), 7.42 (1H,d, J=2.4 Hz), 7.46 (1H, m), 8.36 (1H, s).

Example 196

Production of2-{2-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl}ethoxy]ethanol(i) Production of2-{2-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethoxy}ethylbenzoate

A mixture of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (747 mg),2-{2-[(methylsulfonyl)oxy]ethoxy}ethyl benzoate (1.43 g), potassiumcarbonate (931 mg) and N,N-dimethylformamide (12 mL) was stirred at 60°C. for 4 hrs. The reaction mixture was poured into water (30 mL), andthe mixture was extracted with ethyl acetate (50 mL×2). The organiclayers were combined, washed with saturated brine and dried overanhydrous magnesium sulfate. After concentration under reduced pressure,the residue was purified by silica gel column chromatography (eluent,hexane:ethyl acetate=80:20→20:80), and further purified by basic silicagel column chromatography (eluent, hexane:ethyl acetate=90:10→40:60) togive the title compound (533 mg).

¹H-NMR (CDCl₃) δ: 2.67 (3H, s), 3.75 (2H, m), 4.01 (2H, m), 4.38 (2H,m), 4.87 (2H, t, J=5.8 Hz), 7.38-7.48 (3H, m), 7.91-7.95 (2H, m), 8.11(1H, s), 8.71 (1H, s).

(ii) Production of2-{2-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethoxy}ethanol

A mixture of2-{2-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethoxy}ethylbenzoate (200 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (140 mg),pyridine hydrochloride (96 mg) and 1-methyl-2-pyrrolidone (5 mL) wasstirred at 140° C. for 16.5 hrs. The reaction mixture was poured intosaturated aqueous sodium hydrogen carbonate (30 mL), and extracted withethyl acetate (30 mL×3). The organic layers were combined, washed withsaturated brine and dried over anhydrous magnesium sulfate. Afterconcentration under reduced pressure, the residue was subjected tosilica gel column chromatography (eluent, hexane:ethylacetate=90:10→20:80). The object fraction was concentrated under reducedpressure and the residue was dissolved in methanol (5 mL). 1N Aqueoussodium hydroxide solution (1 mL) was added and the mixture was stirredat room temperature for 11.5 hrs. After concentration of the reactionmixture under reduced pressure, water (30 mL) was added, and the mixturewas extracted with ethyl acetate (45 mL×2). The organic layer was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent, hexane:ethyl acetate=80:20→0:100) and recrystallized fromethanol-ethyl acetate to give the title compound (78 mg).

¹H-NMR (DMSO-d₆) δ: 3.30-3.55 (4H, m), 3.87 (2H, m), 4.67 (1H, m), 4.86(2H, m), 5.26 (2H, s), 7.14-7.35 (4H, m), 7.46 (1H, m), 7.60 (1H, d,J=8.4 Hz), 7.92 (1H, m), 8.18 (1H, s), 8.35 (1H, s), 8.99 (1H, br s).

Example 197

Production of2-{2-[7-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethoxy}ethanol

A mixture of2-{2-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethoxy}ethylbenzoate (328 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (264mg), pyridine hydrochloride (159 mg) and 1-methyl-2-pyrrolidone (7.5 mL)was stirred at 140° C. for 33.5 hrs. The reaction mixture was pouredinto saturated aqueous sodium hydrogen carbonate (15 mL), and extractedwith ethyl acetate (35 mL×2). The organic layers were combined and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was subjected to silica gel column chromatography(eluent, hexane:ethyl acetate=80:20→0:100). The object fraction wasconcentrated under reduced pressure and the residue was dissolved inmethanol (5 mL). 1N Aqueous sodium hydroxide solution (1 mL) was addedand the mixture was stirred at room temperature for 2 hrs. Afterconcentration of the reaction mixture under reduced pressure, water (30mL) was added, and the mixture was extracted with ethyl acetate (40mL×2). The organic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100) andrecrystallized from ethyl acetate-hexane to give the title compound (50mg).

¹H-NMR (DMSO-d₆) δ: 3.40-3.55 (4H, m), 3.88 (2H, m), 4.68 (1H, m), 4.89(2H, m), 7.20-7.24 (2H, m), 7.33 (1H, d, J=8.7 Hz), 7.47 (1H, d, J=7.5Hz), 7.62 (1H, m), 7.77 (1H, m), 8.13 (1H, s), 8.22 (1H, s), 8.44 (1H,m), 9.23 (1H, br s).

Example 198

Production of2-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol(i) Production of 4-phenoxy-6-prop-1-yn-1-ylpyrimidin-5-amine

4-Iodo-6-phenoxypyrimidin-5-amine (5.00 g) was dissolved in a mixedsolvent of N,N-dimethylformamide (100 mL)/triethylamine (50 mL), and1-(trimethylsilyl)-1-propyne (3.3 mL),trans-dichlorobis(triphenylphosphine)palladium(II) (557.7 mg),triphenylphosphine (421.1 mg), copper(I) iodide (303.0 mg) and potassiumfluoride (1.29 g) were sequentially added. The mixture was stirred at60° C. under an argon stream for 16 hrs. The reaction mixture wastreated with saturated aqueous sodium hydrogen carbonate solution andextracted with diethyl ether. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was separated and purified by silicagel column chromatography (eluent, hexane:ethyl acetate=80:20→50:50) togive the title compound (2.64 g) as a orange solid.

¹H-NMR (CDCl₃) δ: 2.19 (3H, s), 4.36 (2H, br s), 7.07-7.22 (2H, m),7.22-7.34 (1H, m), 7.35-7.54 (2H, m), 8.08 (1H, s).

(ii) Production of 6-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine

4-Phenoxy-6-prop-1-yn-1-ylpyrimidin-5-amine (776.0 mg) was dissolved intetrahydrofuran (30 mL) and cooled to 0° C. To this solution was addeddropwise a 1.0 M solution (4 mL) of potassium tert-butoxide intetrahydrofuran, and the mixture was stirred at room temperature for 30min. Water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was separated and purified by silicagel column chromatography (eluent, hexane:ethyl acetate=67:33→20:80) togive the title compound (578.6 mg) as a white solid.

¹H-NMR (CDCl₃) δ: 2.54 (3H, s), 6.44 (1H, q, J=1.0 Hz), 7.21-7.30 (3H,m), 7.41-7.48 (2H, m), 8.47 (1H, s), 8.55 (1H, br s).

(iii) Production of2-[2-(6-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethylbenzoate

6-Methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine (299.9 mg) and2-{2-[(methylsulfonyl)oxy]ethoxy}ethyl benzoate (464.1 mg) weredissolved in N,N-dimethylformamide (7 mL), potassium carbonate (431 mg)was added, and the mixture was stirred at 60° C. for 21 hr. Water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was separated and purified by silica gel column chromatography(eluent, hexane:ethyl acetate=80:20→20:80) to give the title compound(517.8 mg) as a yellow oil.

¹H-NMR (CDCl₃) δ: 2.50 (3H, s), 3.62-3.74 (2H, m), 3.92 (2H, t, J=5 Hz),4.33-4.44 (2H, m), 4.57 (2H, t, J=5 Hz), 6.36 (1H, s), 7.15-7.34 (3H,m), 7.34-7.51 (4H, m), 7.51-7.65 (1H, m), 7.87-8.00 (2H, m), 8.40 (1H,s).

(iv) Production of2-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethylbenzoate

A mixture of2-[2-(6-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethylbenzoate (92.3 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (86.3 mg),pyridine hydrochloride (81.6 mg) and phenol (156.1 mg) was stirred at120° C. for 3 hrs, and at 140° C. for 5.5 hrs. Further, pyridinehydrochloride (77.6 mg) and phenol (188.7 mg) were added, and themixture was stirred at 140° C. for 22.5 hrs. The reaction mixture wasdiluted with dichloromethane, washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was separated and purified by basic silica gel columnchromatography (eluent, hexane:ethyl acetate=50:50→0:100) to give thetitle compound (33.3 mg) as a purple oil.

¹H-NMR (CDCl₃) δ: 2.43 (3H, s), 3.88-3.97 (2H, m), 4.00 (2H, t, J=4.4Hz), 4.42-4.55 (4H, m), 5.04 (2H, s), 6.38 (1H, s), 6.71 (1H, d, J=8.8Hz), 6.93-7.09 (1H, m), 7.13-7.42 (6H, m), 7.46-7.58 (1H, m), 7.65 (1H,d, J=2.6 Hz), 7.74-7.85 (2H, m), 8.40 (1H, s), 8.48 (1H, s).

(v) Production of2-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol

2-{2-[4-({3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethylbenzoate (90.0 mg) was dissolved in methanol (1 mL), 1N aqueous sodiumhydroxide solution (0.3 mL) was added, and the mixture was stirred atroom temperature for 5 hrs. The reaction mixture was neutralized with 1Nhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas separated and purified by basic silica gel column chromatography(eluent, hexane:ethyl acetate=33:67→0:100) to give the title compound(43.9 mg) as a pale-yellow powder.

¹H-NMR (DMSO-d₆) δ 2.45 (3H, s), 3.46-3.52 (4H, m), 3.82 (2H, t, J=4.7Hz), 4.52 (2H, t, J=4.3 Hz), 4.64-4.80 (1H, m), 5.23 (2H, s), 6.30 (1H,s), 7.10-7.24 (2H, m), 7.26-7.38 (2H, m), 7.41-7.55 (2H, m), 7.82 (1H,d, J=2.8 Hz), 8.21 (1H, s), 8.68 (1H, s).

Example 199

Production of2-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol(i) Production of2-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethylbenzoate

The title compound (288.2 mg) was obtained as a pale pink oil by thereaction in the same manner as in Example 198 (iv) using2-[2-(6-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethylbenzoate (271.0 mg), 3-chloro-4-[3-(trifluoromethoxy)phenoxy]aniline(297.3 mg), pyridine hydrochloride (235.0 mg) and phenol (497.9 mg).

¹H-NMR (CDCl₃) δ: 2.45 (3H, s), 3.92-4.00 (2H, m), 4.04 (2H, t, J=4.4Hz), 4.45-4.55 (4H, m), 6.42 (1H, s), 6.75-6.85 (3H, m), 6.85-6.96 (2H,m), 7.19-7.37 (3H, m), 7.45-7.53 (1H, m), 7.75-7.82 (2H, m), 7.85 (1H,d, J=2.8 Hz), 8.46 (1H, s), 8.73 (1H, br s).

(ii) Production of2-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol

The title compound (119.1 mg) was obtained as a white powder by thereaction in the same manner as in Example 198 (v) using2-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethylbenzoate (281.5 mg), 1N aqueous sodium hydroxide solution (0.6 mL) andmethanol (2 mL).

¹H-NMR (DMSO-d₆) δ 2.47 (3H, s), 3.44-3.56 (4H, m), 3.81-3.89 (2H, m),4.56 (2H, t, J=4.5 Hz), 4.71-4.79 (1H, m), 6.35 (1H, s), 6.88-6.95 (2H,m), 7.06-7.14 (1H, m), 7.26 (1H, d, J=9 Hz), 7.50 (1H, t, J=9 Hz), 7.66(1H, dd, J=9 Hz, 2.5 Hz), 8.01 (1H, d, J=2.5 Hz), 8.30 (1H, s), 8.99(1H, br s).

Example 200

Production of4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidine-6-carbonitrile(i) Production of4-(3,3-diethoxyprop-1-yn-1-yl)-6-phenoxypyrimidin-5-amine

The title compound (6.20 g) was obtained as a brown oil by the reactionin the same manner as in Example 9 (iv) using

4-iodo-6-phenoxypyrimidin-5-amine (7.0 g), 3,3-diethoxyprop-1-yne (3.8mL), trans-dichlorobis(triphenylphosphine)palladium(II) (783.3 mg),copper(I) iodide (255.2 mg) and acetonitrile (160 mL)/triethylamine (120mL).

¹H-NMR (CDCl₃) δ: 1.29 (6H, t, J=7.2 Hz), 3.62-3.77 (2H, m), 3.77-3.91(2H, m), 4.48 (2H, br s), 5.56 (1H, s), 7.14-7.21 (2H, m), 7.27-7.33(1H, m), 7.39-7.50 (2H, m), 8.11 (1H, s).

(ii) Production of6-(diethoxymethyl)-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine

4-(3,3-Diethoxyprop-1-yn-1-yl)-6-phenoxypyrimidin-5-amine (2.30 g) wasdissolved in 1-methyl-2-pyrrolidone (7.5 mL), and the mixture was cooledto 0° C. A solution (7.6 mL) of potassium tert-butoxide in 1.0 Mtetrahydrofuran was added dropwise to this solution, and the mixture wasstirred at 0° C. for 30 min. and at room temperature for 1.5 hrs. Waterwas added to the reaction mixture and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was separated and purified by silica gel columnchromatography (eluent, hexane:ethyl acetate=90:10-50:50) to give thetitle compound (1.34 g) as a pale orange solid.

¹H-NMR (CDCl₃) δ: 1.29 (6H, t, J=7.1 Hz), 3.52-3.75 (4H, m), 5.78 (1H,s), 6.66 (1H, br d, J=2.2 Hz), 7.26-7.34 (3H, m), 7.42-7.52 (2H, m),8.52 (1H, s), 8.95 (1H, br s).

(iii) Production of 4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carbaldehyde

6-(Diethoxymethyl)-4-phenoxy-5H-pyrrolo[3,2-O]pyrimidine (3.15 g) wasdissolved in tetrahydrofuran (40 mL), 1N hydrochloric acid (40 mL) wasadded, and the mixture was stirred at room temperature for 2 hrs. Thereaction mixture was neutralized with 1N aqueous sodium hydroxidesolution, and extracted with a mixed solvent of ethylacetate/tetrahydrofuran=1/1. The organic layer was washed with saturatedbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The precipitate was collected by filtration and driedto give the title compound (2.17 g) as a yellow powder.

¹H-NMR (DMSO-d₆) δ: 7.25-7.40 (3H, m), 7.43-7.58 (3H, m), 8.44 (1H, s),10.06 (1H, s), 13.26 (1H, s).

(iv) Production of 4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carboxylicacid

4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carbaldehyde (2.17 g) wasdissolved in dimethyl sulfoxide (21 mL) and a solution of sodiumdihydrogen phosphate (5.45 g) in water (14 mL) was added. A solution ofsodium chlorite (2.06 g) in water (14 mL) was added dropwise to thissolution, and the mixture was stirred for 2 hrs. Saturated aqueoussodium hydrogen carbonate solution was gradually added to the reactionmixture, and the pH of the solution was adjusted to 2-3 with 1Nhydrochloric acid. The resultant precipitate was collected byfiltration, washed with water and diisopropyl ether and dried to givethe title compound (2.40 g) as a white powder.

¹H-NMR (DMSO-d₆) δ: 7.09 (1H, s), 7.23-7.36 (3H, m), 7.41-7.54 (2H, m),8.36 (1H, s), 12.82 (1H, s).

(v) Production of 4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide

Thionyl chloride (7 mL) was added to4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carboxylic acid (465.0 mg) andthe mixture was stirred at 75° C. for 2 hrs. The reaction mixture wasconcentrated under reduced pressure and suspended in tetrahydrofuran (10mL). The above-mentioned suspension was gradually added to aqueousammonia (20 mL) and the precipitate was collected by filtration. Thefiltrate was extracted with a mixed solvent of ethylacetate/tetrahydrofuran=1/1, washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theprecipitate was collected by filtration, combined with the precipitatecollected earlier by filtration and dried to give the title compound(427.4 mg) as a pale-yellow powder.

¹H-NMR (DMSO-d₆) δ: 7.25 (1H, s), 7.27-7.35 (3H, m), 7.39-7.57 (2H, m),7.75 (1H, s), 8.17 (1H, s), 8.36 (1H, s), 12.58 (1H, s).

(vi) Production of 4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carbonitrile

4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide (1.67 g) wassuspended in phosphorus oxychloride (20 mL), and the suspension wasstirred at 70° C. for 3 hrs. The reaction mixture was concentrated underreduced pressure, and the residue was dissolved in tetrahydrofuran (25mL). Water and aqueous ammonia were added to the solution, and themixture was extracted with a mixed solvent of ethylacetate/tetrahydrofuran=1/1. The organic layer was washed with saturatedbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was separated and purified by silica gelcolumn chromatography (eluent, hexane:ethyl acetate=90:10→67:33) to givethe title compound (1.07 g) as a pale-yellow powder.

¹H-NMR (CDCl₃) δ: 7.29-7.39 (3H, m), 7.46-7.55 (2H, m), 7.59 (1H, s),8.47 (1H, s), 13.76 (1H, s).

(vii) Production of2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-6-cyano-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethylbenzoate

4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carbonitrile (240.4 mg) wasdissolved in N,N-dimethylformamide (5 mL), and2-{2-[(methylsulfonyl)oxy]ethoxy}ethyl benzoate (354.1 mg) and potassiumcarbonate (354.8 mg) were added. The title compound (266.5 mg) wasobtained as a colorless oil by the reaction in the same manner as inExample 198 (iii) using the mixture prepared above.

¹H-NMR (CDCl₃) δ: 3.73-3.79 (2H, m), 3.96 (2H, t, J=4.9 Hz), 4.37-4.43(2H, m), 4.83 (2H, t, J=4.9 Hz), 7.17 (1H, s), 7.18-7.23 (2H, m),7.27-7.35 (1H, m), 7.36-7.49 (4H, m), 7.51-7.58 (1H, m), 7.85-7.92 (2H,m), 8.49 (1H, s).

(viii) Production of2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-6-cyano-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethylbenzoate

The title compound (282.6 mg) was obtained as a yellow oil by thereaction in the same manner as in Example 198 (iv) using2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-6-cyano-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethylbenzoate (261.5 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline(264.4 mg), pyridine hydrochloride (221.6 mg) and phenol (461.6 mg).

¹H-NMR (CDCl₃) δ: 3.96-4.06 (2H, m), 4.16-4.22 (2H, m), 4.45-4.54 (2H,m), 4.68-4.79 (2H, m), 6.80 (1H, d, J=8.8 Hz), 7.01-7.09 (1H, m),7.14-7.20 (1H, m), 7.24 (1H, s), 7.27-7.53 (6H, m), 7.68-7.76 (2H, m),7.92 (1H, d, J=2.5 Hz), 8.53 (1H, s), 8.95 (1H, s).

(ix) Production of4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidine-6-carbonitrile

The title compound (143.2 mg) was obtained as a white powder by thereaction in the same manner as in Example 198 (v) using2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-6-cyano-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethylbenzoate (282.6 mg), 1N aqueous sodium hydroxide solution (0.6 mL) andmethanol (3 mL).

¹H-NMR (CDCl₃) δ: 1.77 (1H, t, J=4.4 Hz), 3.74-3.88 (4H, m), 4.08-4.16(2H, m), 4.70-4.80 (2H, m), 7.05-7.15 (2H, m), 7.16-7.21 (1H, m), 7.25(1H, s), 7.30-7.36 (1H, m), 7.43 (1H, t, J=7.8 Hz), 7.67 (1H, dd, J=8.8Hz, 2.8 Hz), 7.96 (1H, d, J=2.8 Hz), 8.58 (1H, s), 9.03 (1H, s).

Example 201

Production of2-{3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propoxy}ethanolhydrochloride (i) Production of3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]propyl methanesulfonate

60% Sodium hydride (8.05 g) was suspended in N,N-dimethylformamide (80mL), and the suspension was cooled to 0° C. A solution ofpropane-1,3-diol (7.2 mL) in N,N-dimethylformamide (10 mL) was addeddropwise, and the mixture was stirred at 0° C. for 1 hr. A solution of2-(2-bromoethoxy)tetrahydro-2H-pyran (4.0 mL) in N,N-dimethylformamide(10 mL) was added dropwise to the reaction solution, and the mixture wasstirred at 0° C. for 2 hrs.

Saturated aqueous ammonium chloride solution was added to the reactionmixture, and the mixture was extracted with diethyl ether and ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was dissolved in ethyl acetate (100 mL), and triethylamine (9mL) and methanesulfonyl chloride (2.3 mL) were added. The mixture wasstirred at room temperature for 3 hrs. Water was added to the reactionmixture and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue wasseparated and purified by silica gel column chromatography (eluent,hexane:ethyl acetate=80:20→20:80) to give the title compound (3.78 g) asa colorless oil.

¹H-NMR (CDCl₃) δ: 1.45-1.66 (4H, m), 1.66-1.92 (2H, m), 1.96-2.09 (2H,m), 3.02 (3H, s), 3.45-3.68 (6H, m), 3.81-3.94 (2H, m), 4.36 (2H, t,J=6.2 Hz), 4.62 (1H, dd, J=4.4 Hz, 2.7 Hz).

(ii) Production of4-chloro-5-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]propyl}-5H-pyrrolo[3,2-d]pyrimidine

4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (203.6 mg),3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]propyl methanesulfonate (559.3mg) was dissolved in N,N-dimethylformamide (4 mL), cesium carbonate(1.30 g) was added, and the mixture was stirred at 40° C. for 4.5 hrs.Water was added to the reaction mixture and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was separated and purified by silica gel columnchromatography (eluent, hexane:ethyl acetate=67:33→20:80) to give thetitle compound (380.2 mg) as a colorless oil.

¹H-NMR (CDCl₃) δ: 1.44-1.70 (4H, m), 1.70-1.95 (2H, m), 1.95-2.24 (2H,m), 3.23-3.43 (2H, m), 3.45-3.69 (2H, m), 3.78-4.02 (2H, m), 4.53-4.75(3H, m), 6.69 (1H, d, J=3.3 Hz), 7.66 (1H, d, J=3.3 Hz), 8.69 (1H, s).

(iii) Production of2-{3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propoxy}ethanolhydrochloride

4-Chloro-5-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]propyl}-5H-pyrrolo[3,2-d]pyrimidine(380.2 mg) was dissolved in isopropyl alcohol (7 mL),3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (419.2 mg) was added, andthe mixture was stirred at 80° C. for 18 hrs. Saturated aqueous sodiumhydrogen carbonate solution was added to the reaction mixture and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was separated andpurified by silica gel column chromatography (eluent, hexane:ethylacetate=50:50→0:100), and the mixture was dissolved in ethyl acetate (4mL). 4N Hydrochloric acid-ethyl acetate (0.3 mL) was added to thissolution, and the precipitate was collected by filtration, and dried togive the title compound (398.2 mg) as a white solid.

¹H-NMR (CDCl₃) δ: 1.86-2.02 (2H, m), 3.22 (2H, t, J=5.8 Hz), 3.27-3.40(2H, m), 3.41-3.55 (2H, m), 4.53-4.69 (2H, m), 6.50 (1H, d, J=3.0 Hz),7.16-7.26 (2H, m), 7.30 (1H, d, J=8.9 Hz), 7.47 (1H, d, J=7.7 Hz),7.56-7.76 (2H, m), 7.97 (1H, s), 8.35 (1H, s), 8.61 (1H, s).

Example 202

Production of2-[4-({3-chloro-4-{3-(trifluoromethyl)phenoxy}phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]-N-[2-(methylsulfonyl)ethyl]acetamide(i) Production of ethyl[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]acetate

The title compound (221.2 mg) was obtained as an orange oil by thereaction in the same manner as in Example 201 (iii) using ethyl(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)acetate (119.3 mg),3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (171.3 mg) and isopropylalcohol (3 mL).

¹H-NMR (CDCl₃) δ: 1.37 (3H, t, J=7 Hz), 4.37 (2H, q, J=7 Hz), 4.98 (2H,s), 6.66 (1H, d, J=3.3 Hz), 7.09 (1H, d, J=8.8 Hz), 7.09-7.14 (1H, m),7.17-7.22 (1H, m), 7.24 (1H, d, J=3.3 Hz), 7.32 (1H, d, J=7.8 Hz), 7.42(1H, t, J=7.8 Hz), 7.53 (1H, dd, J=8.8 Hz, 2.8 Hz), 7.83 (1H, d, J=2.8Hz), 8.52-8.63 (2H, m)

(ii) Production of[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]aceticacid

Ethyl[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]acetate(221.2 mg) was dissolved in a mixed solvent of tetrahydrofuran (1.5mL)/ethanol (1.5 mL), 1N aqueous sodium hydroxide solution (0.6 mL) wasadded, and the mixture was stirred at room temperature for 30 min. Thereaction mixture was adjusted to pH 2-3 with 1N hydrochloric acid andextracted with a mixed solvent of ethyl acetate/tetrahydrofuran=1/1. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas collected by filtration and dried to give the title compound (169.8mg) as a yellow powder.

¹H-NMR (DMSO-d₆) δ: 5.62 (2H, s), 6.70 (1H, d, J=3.0 Hz), 7.22-7.31 (2H,m), 7.35 (1H, d, J=8.8 Hz), 7.51 (1H, d, J=8 Hz), 7.59 (1H, dd, J=8.8Hz, 2.5 Hz), 7.65 (1H, t, J=8 Hz), 7.86 (1H, d, J=2.5 Hz), 7.95 (1H, d,J=3.0 Hz), 8.70 (1H, s), 9.99 (1H, s).

(iii) Production of2-[4-({3-chloro-4-{3-(trifluoromethyl)phenoxy}phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]-N-[2-(methylsulfonyl)ethyl]acetamide

[4-({3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]aceticacid (149.3 mg) was dissolved in N,N-dimethylformamide (1.6 mL),2-(methylsulfonyl)ethanamine (60.3 mg), 1H-1,2,3-benzotriazol-1-ol (67.8mg), triethylamine (0.15 mL) andN-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (93.0 mg)were added, and the mixture was stirred at room temperature for 17 hrs.Moreover, 2-(methylsulfonyl)ethanamine (120.6 mg),1H-1,2,3-benzotriazol-1-ol (134.6 mg), triethylamine (0.3 mL) andN-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (181.4mg) were added, and the mixture was stirred at room temperature for 24hrs. Water was added to the reaction mixture and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was separated and purified by silicagel column chromatography (eluent, ethyl acetate:methanol=100:0→90:10),and basic silica gel column chromatography (eluent, hexane:ethylacetate=33:67→0:100→ethyl acetate:methanol=90:10) to give the titlecompound (20.3 mg) as a white powder.

¹H-NMR (DMSO-d₆) δ: 2.98 (3H, s), 3.27 (2H, t, J=6.9 Hz), 3.50-3.61 (2H,m), 5.12 (2H, s), 6.54 (1H, d, J=3.0 Hz), 7.15-7.26 (2H, m), 7.33 (1H,d, J=8.8 Hz), 7.47 (1H, d, J=8.0 Hz), 7.56-7.68 (3H, m), 8.04 (1H, d,J=2.5 Hz), 8.38 (1H, s), 9.07 (1H, t, J=5.8 Hz), 9.97 (1H, s).

Example 203

Production of4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]but-2-yn-1-ol(i) Production of 4-{[tert-butyl(dimethyl)silyl]oxy}but-2-yn-1-ol

60% Sodium hydride (1.39 g) was suspended in tetrahydrofuran (50 mL),and the suspension was cooled to 0° C., a solution of but-2-yne-1,4-diol(3.0 g) in tetrahydrofuran (20 mL) was added dropwise, and the mixturewas stirred at room temperature for 1 hr. tert-Butyldimethylsilylchloride (5.26 g) was added to the reaction mixture, and the mixture wasstirred at room temperature for 24 hrs. Water was added to the reactionmixture and the mixture was extracted with diethyl ether. The organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue wasseparated and purified by silica gel column chromatography (eluent,hexane:ethyl acetate=100:0→80:20) to give the title compound (1.48 g) asa colorless oil.

¹H-NMR (CDCl₃) δ: 0.12 (6H, s), 0.91 (9H, s), 1.60-1.66 (1H, m),4.27-4.33 (2H, m), 4.36 (2H, t, J=1.8 Hz).

(ii) Production of 4-{[tert-butyl(dimethyl)silyl]oxy}but-2-yn-1-ylmethanesulfonate

4-{[Tert-butyl(dimethyl)silyl]oxy}but-2-yn-1-ol (701.4 mg) was dissolvedin ethyl acetate (15 mL), and the solution was cooled to 0° C.Triethylamine (1.1 mL) and methanesulfonyl chloride (0.3 mL) were added,and the mixture was stirred at 0° C. for 3 hrs. Water was added to thereaction mixture and the mixture was extracted with diethyl ether. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas separated and purified by silica gel column chromatography (eluent,hexane:ethyl acetate=90:10→50:50) to give the title compound (469.7 mg)as a colorless oil.

¹H-NMR (CDCl₃) δ: 0.12 (6H, s), 0.91 (9H, s), 3.12 (3H, s), 4.37 (2H, t,J=1.9 Hz), 4.89 (2H, t, J=1.9 Hz).

(iii) Production of5-(4-{[tert-butyl(dimethyl)silyl]oxy}but-2-yn-1-yl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidine

The title compound (431.1 mg) was obtained as a yellow oil by thereaction in the same manner as in Example 201 (ii) using4-chloro-5H-pyrrolo[3,2-d]pyrimidine (211.9 mg),4-{[tert-butyl(dimethyl)silyl]oxy}but-2-yn-1-yl methanesulfonate (464.0mg), cesium carbonate (672.7 mg) and N,N-dimethylformamide (5 mL).

¹H-NMR (CDCl₃) δ: 0.07 (6H, s), 0.87 (9H, s), 4.35 (2H, t, J=2 Hz), 5.33(2H, t, J=2 Hz), 6.76 (1H, d, J=3.3 Hz), 7.69 (1H, d, J=3.3 Hz), 8.72(1H, s).

(iv) Production of4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]but-2-yn-1-ol

5-(4-{[Tert-butyl(dimethyl)silyl]oxy}but-2-yn-1-yl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidine(408.3 mg) was dissolved in isopropyl alcohol (7 mL),3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (421.0 mg) was added, andthe mixture was stirred at 80° C. for 6 hrs. Water was added to thereaction mixture and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The obtainedoil was dissolved in tetrahydrofuran (6 mL), a 1.0 M solution (2 mL) oftetrabutylammonium fluoride in tetrahydrofuran was added, and themixture was stirred at room temperature for 1 hr. To the reactionmixture was added saturated aqueous ammonium chloride solution and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was separated andpurified by silica gel column chromatography (eluent, hexane:ethylacetate=67:33→20:80) and crystallized from hexane/ethyl acetate to givethe title compound (425 mg) as white crystals.

¹H-NMR (CDCl₃) δ: 4.07-4.13 (1H, m), 4.45-4.52 (2H, m), 5.01-5.06 (2H,m), 6.44 (1H, d, J=3.3 Hz), 7.06-7.16 (3H, m), 7.18-7.22 (1H, m), 7.33(1H, d, J=8 Hz), 7.43 (1H, t, J=8 Hz), 7.57 (1H, dd, J=8.8 Hz, 2.5 Hz),7.82 (1H, s), 7.95 (1H, d, J=2.5 Hz), 8.40 (1H, s).

Example 204

Production of(2E)-4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]but-2-en-1-ol

70% Sodium bis(2-methoxyethoxy)aluminum hydride in toluene solution (0.8mL) was dissolved in tetrahydrofuran (4 mL), and the solution was cooledto 0° C. A solution of4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]but-2-yn-1-ol(262.4 mg) in tetrahydrofuran (10 mL) was added dropwise, and themixture was stirred at 0° C. for 2 hrs. To the reaction mixture wasadded 10% aqueous potassium carbonate solution and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was separated and purified by silicagel column chromatography (eluent, hexane:ethyl acetate=33:67→0:100) andcrystallized from hexane/ethyl acetate to give the title compound (195.9mg) as white crystals.

¹H-NMR (DMSO-d₆) δ: 3.81-3.92 (2H, m), 4.75 (1H, t, J=5.5 Hz), 5.17 (2H,m), 5.56 (1H, br d, J=15 Hz), 5.80 (1H, br d, J=15 Hz), 6.53 (1H, d,J=3.0 Hz), 7.16-7.26 (2H, m), 7.30 (1H, d, J=8.8 Hz), 7.47 (1H, d, J=7.7Hz), 7.57-7.74 (3H, m), 7.98 (1H, d, J=2.2 Hz), 8.36 (1H, s), 8.48 (1H,s).

Example 205

Production of3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propane-1,2-diol(i) Production of3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propane-1,2-diyl dibenzoate

A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg),3-bromopropane-1,2-diyl dibenzoate (1.77 g), cesium carbonate (1.59 g)and N,N-dimethylformamide (6.5 mL) was stirred at 80° C. for 4 hrs. Thereaction mixture was diluted with ethyl acetate (100 mL) and washed withwater (80 mL). The organic layer was separated, dried over magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=90/10→40/60) to give the title compound (401 mg) as a whitepowder.

¹H-NMR (CDCl₃) δ 4.58 (1H, dd, J=5 Hz, 12 Hz), 4.73 (1H, dd, J=5 Hz, 12Hz), 4.84 (1H, dd, J=9 Hz, 15 Hz), 5.11 (1H, dd, J=15 Hz, 5 Hz), 5.84(1H, m), 6.69 (1H, d, J=3 Hz), 7.3-7.7 (7H, m), 7.91 (2H, m), 8.02 (2H,m), 8.69 (1H, s).

(ii) Production of3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propane-1,2-diol

The title compound (180 mg) was obtained as colorless crystals by themethod in the same manner as in Example 183 using3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propane-1,2-diyl dibenzoate(250 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (280 mg) and1-methyl-2-pyrrolidone (1.14 mL).

¹H-NMR (DMSO-d₆) δ 3.47 (2H, m), 3.94 (1H, m), 4.50 (2H, m), 5.18 (1H,br s), 6.52 (2H, d, J=3 Hz), 7.20 (2H, m), 7.33 (1H, d, J=9 Hz), 7.45(1H, d, J=8 Hz), 7.64 (3H, m), 8.04 (1H, d, J=3 Hz), 8.35 (1H, s), 10.03(1H, br s).

Example 206

Production of2-(2-{4-[{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}(methyl)amino]-5H-pyrrolo[3,2-d]pyrimidin-5-yl}ethoxy)ethanol

The title compound (127 mg) was obtained by the method in the samemanner as in Example 183 using2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate(150 mg), 3-chloro-N-methyl-4-[3-(trifluoromethyl)phenoxy]aniline (196mg) and 1-methyl-2-pyrrolidone (0.863 mL).

¹H-NMR (CDCl₃) δ 3.38 (2H, t, J=4.5 Hz), 3.48 (2H, t, J=4.5 Hz), 3.58(3H, s), 3.62 (2H, m), 4.00 (2H, t, J=5 Hz), 5.08 (1H, br s), 6.64 (1H,dd, J=3 Hz, 9 Hz), 6.70 (1H, d, J=3 Hz), 6.72 (1H, s), 6.97 (2H, m),7.09 (2H, m), 7.40 (2H, m), 8.79 (1H, s).

Example 207

Production ofN-(2-{4-[{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}(methyl)amino]-5H-pyrrolo[3,2-d]pyrimidin-5-yl}ethyl)-2-(methylsulfonyl)acetamidehydrochloride

A mixture of tert-butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (297 mg),3-chloro-N-methyl-4-[3-(trifluoromethyl)phenoxy]aniline (453 mg) and1-methyl-2-pyrrolidone (1.99 mL) was stirred at 120° C. for 16 hrs. Tothe reaction mixture was added 2N hydrochloric acid (1 mL), and themixture was stirred at 80° C. for 2.5 hrs. The reaction mixture wasdiluted with ethyl acetate (80 mL) and washed with aqueous sodiumhydrogen carbonate (30 mL). The organic layer was separated, dried overmagnesium sulfate and evaporated under reduced pressure. The residue,2-(methylsulfonyl)acetic acid (207 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (429 mg),1-hydroxybenzotriazole monohydrate (304 mg), triethylamine (0.697 mL)and N,N-dimethylformamide (7.69 mL) were reacted in the same manner asin Example 155 (iv). The obtained compound was treated with 4Nhydrochloric acid/ethyl acetate to give the title compound (149 mg) ascolorless crystals.

¹H-NMR (DMSO-d₆) δ 3.02 (3H, s), 3.20 (2H, s), 3.51 (2H, m), 3.71 (3H,s), 3.90 (2H, s), 6.72 (1H, d, J=3 Hz), 7.2-7.4 (4H, m), 7.52 (1H, d,J=8 Hz), 7.68 (2H, m), 7.86 (1H, d, J=2 Hz), 8.40 (1H, m), 8.94 (1H, s).

Example 208

Production ofN-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-3-hydroxy-3-methylbutanamide

The title compound (145 mg) was obtained as crystals by the reaction inthe same manner as in Example 155 (iv) using5-(2-aminoethyl)-N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (200 mg) and 3-hydroxy-3-methylbutyric acid (104 mg).

¹H-NMR (CDCl₃) δ: 1.33 (6H, s), 2.49 (2H, s), 3.55-3.7 (2H, m), 4.4-4.55(2H, m), 6.60 (1H, d, J=3.4 Hz), 6.85-7.1 (4H, m), 7.1-7.3 (2H, m),7.7-7.8 (1H, m), 8.05 (1H, d, J=2.6 Hz), 8.52 (1H, s), 8.64 (1H, s).

Example 209

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(isopropylsulfonyl)acetamide

5-(2-Aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (300 mg) and 4-methylmorpholine (3.0 mL) were dissolvedin tetrahydrofuran (7.0 mL), chloroacetyl chloride (0.7 mL) was added,and the mixture was stirred at 0° C. for 2 hrs. To the reaction mixturewas added saturated aqueous sodium hydrogen carbonate under ice-coolingand the mixture was extracted with ethyl acetate. The extract was driedover magnesium sulfate and concentrated, and the residue was dissolvedin a mixed solvent of N,N-dimethylformamide (3.5 mL) and tetrahydrofuran(6.0 mL). To the mixture was added sodium 2-methylpropane-2-thiolate(180 mg), and the mixture was stirred at room temperature for 1 hr. Tothe reaction mixture was added saturated aqueous sodium hydrogencarbonate under ice-cooling and the mixture was extracted with ethylacetate.

The extract was dried over magnesium sulfate and concentrated, and theresidue was separated and purified by silica gel column chromatography(eluent, ethyl acetate:methanol=100:0→ethyl acetate:methanol=90:10) togive an oil. The title compound (165 mg) was obtained as crystals by thereaction in the same manner as in Example 172 (ii) using the oilobtained above and titanium tetraisopropoxide (0.15 mL), methanol (0.52mL) and 70% aqueous tert-butyl hydroperoxide solution (12.0 mL).

¹H-NMR (DMSO-d₆) δ: 1.24 (6H, d, J=6.8 Hz), 3.45-3.58 (3H, m), 4.03 (2H,s), 4.56 (2H, m), 6.52 (1H, m), 7.20-7.99 (8H, m), 8.35 (1H, s), 8.72(1H, s).

Example 210

Production ofN-{2-[4-{(3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-[(cyclopentyl)sulfonyl]acetamide

The title compound (115 mg) was obtained as crystals by the reaction inthe same manner as in Example 209 using5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (350 mg), 4-methylmorpholine (3.50 mL), chloroacetylchloride (0.9 mL), sodium cyclopentanethiolate (890 mg), titaniumtetraisopropoxide (0.25 mL), methanol (0.55 mL) and 70% aqueoustert-butyl hydroperoxide solution (15.0 mL).

¹H-NMR (DMSO-d₆) δ: 1.50-1.63 (4H, m), 1.89 (4H, m), 3.47 (2H, m), 3.79(1H, m), 3.99 (2H, s), 4.56 (2H, m), 6.52 (1H, m), 7.20-7.99 (8H, m),8.35 (1H, s), 8.72 (1H, s).

Example 211

Production ofN-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-[2-(2,2,2-trifluoroethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine

The title compound (175 mg) was obtained as crystals by the reaction inthe same manner as in Example 171 using4-chloro-5H-pyrrolo[3,2-d]pyrimidine (340 mg), potassium carbonate (530mg) and 2-(2,2,2-trifluoroethoxy)ethyl methanesulfonate (550 mg).

¹H-NMR (DMSO-d₆) δ: 3.91-4.09 (4H, m), 3.73-3.76 (2H, m), 6.53 (1H, d,J=3 Hz), 7.21-7.92 (8H, m), 8.36 (1H, s), 8.62 (1H, s).

Example 212

Production of(2E)-N-[(2E)-3-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl)prop-2-en-1-yl]-4-(dimethylamino)but-2-enamide(i) Production ofN-(4,6-diiodopyrimidin-5-yl)-2,2,2-trifluoro-N-methylacetamide

4,6-Diiodopyrimidin-5-amine (20 g) was dissolved in dichloromethane (200mL), and trifluoroacetic anhydride (47.3 mL) and triethylamine (8.04 mL)were successively added dropwise. The mixture was stirred at roomtemperature for 1 hr, and the reaction mixture was concentrated underreduced pressure. The residue was dissolved in methanol (150 mL), andconcentrated again under reduced pressure to give a colorless solid. Theobtained solid was dissolved in N,N-dimethylformamide (106 mL),potassium carbonate (15.9 g) and iodomethane (10.8 mL) were added, andthe mixture was stirred at room temperature for 16 hrs. The reactionmixture was diluted with diethyl ether (400 mL) and washed with water(400 mL). The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure to give the title compound (25.1 g)as a colorless solid.

¹H-NMR (CDCl₃) δ: 3.34 (2H, s), 3.48 (1H, s), 8.44 (1H, d, J=2 Hz).

(ii) Production ofN-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-6-iodopyrimidin-5-yl)-2,2,2-trifluoro-N-methylacetamide

N-(4,6-Diiodopyrimidin-5-yl)-2,2,2-trifluoro-N-methylacetamide (3 g) and3-(4-amino-2-chlorophenoxy)benzonitrile (1.69 g) were dissolved in1-methyl-2-pyrrolidone (11.4 mL), and the mixture was stirred withheating at 100° C. for 16 hrs. To the reaction mixture was added aqueoussodium hydrogen carbonate (80 mL) and the mixture was extracted withethyl acetate (100 mL×2). The organic layer was washed with saturatedbrine (80 mL), dried over magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent, hexane:ethyl acetate=90:10->hexane:ethylacetate=50:50) and crystallized from diisopropyl ether to give the titlecompound (1.67 g) as colorless crystals.

¹H-NMR (CDCl₃) δ: 3.39 (3H, s), 7.1-7.6 (6H, m), 7.90 (1H, d, J=3 Hz),8.37 (1H, s).

(iii) Production of3-(2-chloro-4-{[6-iodo-5-(methylamino)pyrimidin-4-yl]amino}phenoxy)benzonitrile

To a solution ofN-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-6-iodopyrimidin-5-yl)-2,2,2-trifluoro-N-methylacetamide(1.0 g) in isopropanol-tetrahydrofuran (5.0 mL-10 mL) was added sodiumborohydride (70 mg) at room temperature. The mixture was stirred at roomtemperature for 1.5 hrs, and ethyl acetate was added. The mixture waswashed with water and saturated brine and the organic layer was driedover magnesium sulfate. After concentration under reduced pressure, theresidue was separated and purified by silica gel column chromatography(eluent, hexane:ethyl acetate=4:1-3:2) to give the title compound (755mg) as a white amorphous solid.

¹H-NMR (CDCl₃) δ: 2.72 (3H, d, J=6.3 Hz), 2.86-2.98 (1H, m), 7.15-7.21(3H, m), 7.31-7.45 (2H, m), 7.58 (1H, dd, J=9.0, 2.7 Hz), 7.73 (1H, brs), 7.99 (1H, d, J=2.7 Hz), 8.20 (1H, s).

(iv) Production of tert-butyl{(2E)-5-[6-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5-(methylamino)pyrimidin-4-yl]pent-2-en-4-yn-1-yl}carbamate

The title compound (366 mg) was obtained as brown powder crystals by thereaction in the same manner as in Example 81 (ii) using3-(2-chloro-4-{[6-iodo-5-(methylamino)pyrimidin-4-yl]amino}phenoxy)benzonitrile(755 mg), tert-butyl pent-2-en-4-ynylcarbamate (0.43 g),bis(triphenylphosphine)palladium(II) dichloride (55.5 mg), copper(I)iodide (18 mg), acetonitrile (16 mL) and triethylamine (12 mL).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.78 (3H, d, J=6.3 Hz), 3.15-3.27 (1H,m), 3.84-3.95 (2H, m), 4.53-4.65 (1H, m), 5.84-5.93 (1H, m), 6.34-6.43(1H, m), 7.09 (1H, d, J=8.7 Hz), 7.10-7.22 (2H, m), 7.32-7.44 (2H, m),7.55 (1H, br s), 7.59 (1H, dd, J=8.7, 2.7 Hz), 7.99 (1H, d, J=2.7 Hz),8.46 (1H, s).

(v) Production of tert-butyl[(2E)-3-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl)prop-2-en-1-yl]carbamate

The title compound (200 mg) was obtained as pale-yellow crystals by thereaction in the same manner as in Example 81 (iii) using tert-butyl{(2E)-5-[6-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5-(methylamino)pyrimidin-4-yl]pent-2-en-4-yn-1-yl}carbamate(366 mg), copper(I) iodide (13 mg) and N,N-dimethylformamide (4.0 mL).

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 3.92-4.03 (5H, m), 4.71-4.86 (1H, m),6.31-6.45 (1H, m), 6.56 (1H, d, J=15.9 Hz), 6.67 (1H, s), 6.74 (1H, s),7.06-7.22 (3H, m), 7.31-7.46 (3H, m), 7.75 (1H, d, J=2.7 Hz), 8.49 (1H,s).

(vi) Production of3-[4-({6-[(1E)-3-aminoprop-1-en-1-yl]-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl}amino)-2-chlorophenoxy]benzonitriledihydrochloride

The title compound (170 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 81 (iv) using tert-butyl[(2E)-3-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl)prop-2-en-1-yl]carbamate(190 mg), 2N hydrochloric acid (4.5 mL) and tetrahydrofuran (9.0 mL).

¹H-NMR (DMSO-d₆) δ: 3.75 (2H, t, J=5.3 Hz), 4.17 (3H, s), 6.62-6.72 (1H,m), 6.87 (1H, s), 7.13 (1H, d, J=16.5 Hz), 7.25-7.34 (2H, m), 7.43-7.46(1H, m), 7.55-7.67 (3H, m), 7.93 (1H, d, J=2.4 Hz), 8.16-8.31 (3H, m),8.64 (1H, s), 9.83 (1H, br s).

(vii) Production of(2E)-N-[(2E)-3-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl)prop-2-en-1-yl]-4-(dimethylamino)but-2-enamide

The title compound (74 mg) was obtained as pale-yellow crystals by thereaction in the same manner as in Example 82 using3-[4-({6-[(1E)-3-aminoprop-1-en-1-yl]-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl}amino)-2-chlorophenoxy]benzonitriledihydrochloride (160 mg), (2E)-4-(dimethylamino)but-2-enoic acidhydrochloride (182 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (420 mg), 1-hydroxybenzotriazole monohydrate (340 mg),triethylamine (0.80 mL) and N,N-dimethylformamide (5.0 mL).

¹H-NMR (DMSO-d₆) δ: 2.15 (6H, s), 3.00 (2H, dd, J=6.0, 1.2 Hz),3.95-4.08 (5H, m), 6.05-6.14 (1H, m), 6.42-6.53 (1H, m), 6.60 (1H, dt,J=15.6, 6.6 Hz), 6.72 (1H, s), 6.78 (1H, d, J=15.6 Hz), 7.20-7.28 (2H,m), 7.39-7.43 (1H, m), 7.53-7.59 (2H, m), 7.60-7.68 (1H, m), 7.68-7.92(1H, m), 8.28 (1H, s), 8.32 (1H, t, J=5.4 Hz), 8.77 (1H, s).

Example 213

Production of(2E)-N-{[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl]methyl}-4-(dimethylamino)but-2-enamide(i) Production of 4,6-diiodo-N-methylpyrimidin-5-amine

To a solution of 4,6-diiodopyrimidin-5-amine (1.0 g) in tetrahydrofuran(10 mL) was added sodium hydride (60%, 138 mg) under ice-cooling. Themixture was stirred at room temperature for 30 min. To the reactionsystem was added dropwise a solution of methyl methanesulfonate (0.256mL) in tetrahydrofuran (4.0 mL). The mixture was stirred at roomtemperature for 3 hrs and ethyl acetate was added. The mixture waswashed with water and saturated brine and dried over magnesium sulfate.After concentration under reduced pressure, the residue was separatedand purified by silica gel column chromatography (hexane:ethylacetate=9:1→3:1) to give the title compound (600 mg) as pale-yellowcrystals.

¹H-NMR (CDCl₃) δ: 3.02 (3H, d, J=5.7 Hz), 3.71-3.83 (1H, m), 8.04 (1H,s).

(ii) Production ofN4-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-6-iodo-N-5-methylpyrimidine-4,5-diamine

The title compound (552 mg) was obtained as pale-yellow crystals by thereaction in the same manner as in Example 212 (ii) using4,6-diiodo-N-methylpyrimidin-5-amine (600 mg),3-chloro-4-[3-(trifluoromethoxy)phenoxy]aniline (504 mg) and1-methyl-2-pyrrolidone (10 mL).

¹H-NMR (DMSO-d₆) δ: 2.71 (3H, d, J=5.7 Hz), 2.87-2.98 (1H, m), 6.76-6.85(2H, m), 6.90-6.96 (1H, m), 7.09 (1H, d, J=8.7 Hz), 7.29-7.34 (1H, m),7.52-7.56 (1H, m), 7.70 (1H, br s), 7.96 (1H, d, J=1.5 Hz), 8.19 (1H,s).

(iii) Production of tert-butyl{[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl]methyl}carbamate

To a solution ofN4-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-6-iodo-N-5-methylpyrimidine-4,5-diamine(1.53 g), tert-butyl prop-2-ynylcarbamate (0.67 g) and triethylamine(1.19 mL) in acetonitrile (28 mL) were addedbis(triphenylphosphine)palladium(II) dichloride (100 mg) and copper(I)iodide (32.5 mg) at room temperature. Under an argon atmosphere, themixture was stirred at room temperature for 4.5 hrs, heated at 50° C.,and the mixture was stirred for 6 hrs. After concentration under reducedpressure, the residue was separated and purified by silica gel columnchromatography (hexane:ethyl acetate=7:3→3:7→basic silica gel,hexane:ethyl acetate=1:1 ethyl acetate) to give the title compound (1.05g) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 4.04 (3H, s), 4.52 (2H, d, J=6.0 Hz),4.83-4.95 (1H, m), 6.49 (1H, s), 6.76-6.96 (4H, m), 7.08 (1H, d, J=8.7Hz), 7.31 (1H, t, J=8.3 Hz), 7.43 (1H, dd, J=8.3 Hz), 7.78 (1H, d, J=2.4Hz), 8.48 (1H, s).

(iv) Production of6-(aminomethyl)-N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride

The title compound (1.01 g) was obtained as pale-yellow crystals by thereaction in the same manner as in Example 81 (iv) using tert-butyl{[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl]methyl}carbamate(1.05 g), 2N hydrochloric acid (20 mL) and tetrahydrofuran (40 mL).

¹H-NMR (DMSO-d₆) δ: 4.18 (3H, s), 4.39-4.48 (2H, m), 6.89 (1H, s),6.94-6.99 (2H, m), 7.15 (1H, d, J=9.0 Hz), 7.35 (1H, d, J=8.7 Hz),7.50-7.56 (1H, m), 7.67 (1H, dd, J=9.0, 2.4 Hz), 7.94 (1H, d, J=2.4 Hz),8.72 (1H, s), 8.77-8.92 (3H, m), 10.04 (1H, br s).

(v) Production of(2E)-N-{[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl]methyl}-4-(dimethylamino)but-2-enamide

The title compound (105 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 82 using6-(aminomethyl)-N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (200 mg), (2E)-4-(dimethylamino)but-2-enoic acidhydrochloride (124 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (214 mg), 1-hydroxybenzotriazole monohydrate (171 mg),triethylamine (0.52 mL) and N,N-dimethylformamide (5.0 mL).

¹H-NMR (CDCl₃) δ: 2.14 (6H, s), 3.00 (2H, d, J=6.3 Hz), 4.00 (3H, s),4.58 (2H, d, J=5.4 Hz), 6.11 (1H, d, J=15.3 Hz), 6.39 (1H, s), 6.58-6.68(1H, m), 6.87-6.95 (2H, m), 7.04-7.11 (1H, m), 7.25 (1H, d, J=8.7 Hz),7.45-7.51 (1H, m), 7.60-7.68 (1H, m), 7.91 (1H, d, J=2.7 Hz), 8.28 (1H,s), 8.54-8.61 (1H, m), 8.71 (1H, s).

Example 214

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxy-2,2-dimethylpropanamidehydrochloride

A solution of5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (150 mg), 3-hydroxy-2,2-dimethylpropanoic acid (68 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (166 mg),1-hydroxybenzotriazole monohydrate (132 mg) and triethylamine (0.40 mL)in N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 20hrs. Water was added to the reaction system and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by basic silica gel column chromatography (eluent, ethylacetate→methanol:ethyl acetate=15:85). After concentration under reducedpressure, ethyl acetate (2.0 mL) and 4N hydrochloric acid/ethyl acetate(0.5 mL) were added, and the mixture was stirred at room temperature for15 hrs. After concentration under reduced pressure, the precipitatedcrystals were collected by filtration. To a solution of the collectedcrystals in ethanol (2.0 mL) was added 1N aqueous sodium hydroxidesolution at room temperature, and the mixture was stirred for 2 days.The mixture was concentrated under reduced pressure and a solution ofthe residue in ethyl acetate was washed with water and saturated brineand dried over magnesium sulfate. After concentration under reducedpressure, 4N hydrochloric acid/ethyl acetate (0.5 mL) was added to asolution of the residue in ethyl acetate (1.0 mL). After concentrationunder reduced pressure, the precipitated crystals were collected byfiltration. The crystals were washed with diisopropyl ether to give thetitle compound (119 mg) as colorless crystals.

¹H-NMR (DMSO-d₆) δ: 0.96 (6H, s), 3.23-3.52 (4H, m), 4.56-4.68 (2H, m),6.64 (1H, d, J=3.0 Hz), 7.23-7.30 (2H, m), 7.38 (1H, d, J=8.4 Hz), 7.52(1H, d, J=8.1 Hz), 7.61-7.69 (1H, m), 7.72-7.80 (1H, m), 7.85-7.92 (2H,m), 8.00-8.03 (1H, m), 8.70 (1H, s), 9.95-10.06 (1H, m).

Example 215

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)propanamide

To a mixture of5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (150 mg), triethylamine (0.39 mL) and tetrahydrofuran(5.0 mL) was added 2-chloropropionyl chloride (54 μL) at roomtemperature. The mixture was stirred at room temperature for 3 days,water was added and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over magnesiumsulfate. After concentration under reduced pressure, sodiummethanesulfinate (85 mg) and pyridine (67 μL) were added to a solutionof the residue in N,N-dimethylformamide (5.0 mL), and the mixture wasstirred at 70° C. for 2 days. Water was added to the reaction system andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by basic silica gel column chromatography (eluent, ethylacetate→ethyl acetate:methanol=9:1) and recrystallized from ethylacetate-diisopropyl ether to give the title compound (114 mg) ascolorless crystals.

¹H-NMR (CDCl₃) δ: 1.71 (3H, d, J=7.2 Hz), 2.98 (3H, s), 3.63-3.75 (2H,m), 3.81 (1H, q, J=7.2 Hz), 4.44-4.55 (2H, m), 6.64 (1H, d, J=3.0 Hz),7.09 (1H, d, J=8.7 Hz), 7.11-7.18 (2H, m), 7.19-7.25 (2H, m), 7.30-7.36(1H, m), 7.40-7.47 (1H, m), 7.85 (1H, dd, J=8.7, 2.7 Hz), 8.01 (1H, d,J=2.7 Hz), 8.30 (1H, s), 8.54 (1H, s).

Example 216

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide

The title compound (128 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 155 (iv) using5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (150 mg), 2-hydroxy-2-(trifluoromethyl)propionic acid(88.2 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(160 mg), 1-hydroxybenzotriazole monohydrate (128 mg), triethylamine(0.39 mL) and N,N-dimethylformamide (5.0 mL).

¹H-NMR (CDCl₃) δ: 1.68 (3H, s), 3.65-3.77 (2H, m), 3.80-3.89 (1H, m),4.43-4.57 (2H, m), 6.63 (1H, d, J=3.0 Hz), 7.08 (1H, d, J=8.7 Hz),7.11-7.16 (1H, m), 7.19-7.28 (3H, m), 7.30-7.36 (1H, m), 7.40-7.43 (1H,m), 7.79 (1H, dd, J=8.7, 2.4 Hz), 8.08 (1H, d, J=2.4 Hz), 8.31 (1H, s),8.53 (1H, s).

Example 217

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide4-methylbenzenesulfonate

To a solution ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide(150 mg) in ethyl acetate (10 mL) was added 4-methylbenzenesulfonic acidmonohydrate (55.4 mg) at room temperature. The mixture was stirred atroom temperature for 20 hrs, and the solvent was evaporated underreduced pressure. The precipitated crystals were collected by filtrationand washed with ethyl acetate and diisopropyl ether to give the titlecompound (150.3 mg) as colorless crystals.

¹H-NMR (DMSO-d₆) δ: 2.29 (3H, s), 3.07 (3H, s), 3.44-3.60 (2H, m), 4.06(2H, s), 4.61-4.70 (2H, m), 6.66 (1H, d, J=3.0 Hz), 7.11 (2H, d, J=8.4Hz), 7.22-7.28 (2H, m), 7.38 (1H, d, J=8.7 Hz), 7.47 (2H, d, J=8.4 Hz),7.50-7.55 (1H, m), 7.62-7.72 (2H, m), 7.89-7.96 (2H, m), 8.65-8.74 (2H,m), 9.70-9.80 (1H, m).

Example 218

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamidehydrochloride

The title compound (147 mg) was obtained as colorless crystals in thesame manner as in Example 217 usingN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide(150 mg), 4N hydrochloric acid/ethyl acetate (0.13 mL) and ethyl acetate(10-mL).

¹H-NMR (DMSO-d₆) δ: 3.06 (3H, s), 3.35-3.59 (2H, m), 4.07 (2H, s),4.63-4.74 (2H, m), 6.67 (1H, d, J=3.0 Hz), 7.25-7.30 (2H, m), 7.38 (1H,d, J=8.7 Hz), 7.51-7.54 (1H, m), 7.62-7.72 (2H, m), 7.92-7.99 (2H, m),8.70-8.79 (2H, m), 9.78-9.89 (1H, m).

Example 219

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamidemethanesulfonate

The title compound (1.14 g) was obtained as colorless crystals in thesame manner as in Example 217 usingN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide(1.0 g), methanesulfonic acid (0.126 mL) and ethyl acetate (50 mL).

¹H-NMR (DMSO-d₆) δ: 2.30 (3H, s), 3.06 (3H, s), 3.47-3.61 (2H, m), 4.06(2H, s), 4.63-4.72 (2H, m), 6.67 (1H, d, J=3.3 Hz), 7.23-7.29 (2H, m),7.37-7.40 (2H, m), 7.63-7.73 (2H, m), 7.91-7.98 (2H, m), 8.68-8.78 (2H,m), 9.80 (1H, br s).

Example 220

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]-1-methylethyl}-2-(methylsulfonyl)acetamide(i) Production of tert-butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1-methylethyl]carbamate

To a solution of 2-aminopropan-1-ol (1.0 g) in tetrahydrofuran (50 mL)was added di-tert-butyl dicarbonate (3.1 mL) at room temperature. Themixture was stirred at room temperature for 3 days and concentratedunder reduced pressure.

To a solution of the residue and triethylamine (3.7 mL) intetrahydrofuran (30 mL) was added methanesulfonyl chloride (1.54 mL)under ice-cooling, and the mixture was stirred at 30 min. To thereaction system was added aqueous sodium hydrogen carbonate and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over magnesium sulfate. Afterconcentration under reduced pressure,4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.02 g), cesium carbonate (6.49 g)and N,N-dimethylformamide (10 mL) were added to the residue, and themixture was stirred at 40° C. for 3 days. Water was added to thereaction system and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine and dried overmagnesium sulfate. After concentration under reduced pressure, theresidue was separated and purified by silica gel column chromatography(hexane:ethyl acetate=3:1→2:3) to give the title compound (1.16 g) as apale-yellow oil.

¹H-NMR (CDCl₃) δ: 0.93-1.35 (12H, m), 4.02-4.18 (1.5H, m), 4.39-4.53(1.5H, m), 4.57-4.70 (1H, m), 6.74 (1H, d, J=3.0 Hz), 7.50 (1H, d, J=3.0Hz), 8.71 (1H, s).

(ii) Production of5-(2-aminopropyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride

A solution of tert-butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1-methylethyl]carbamate(350 mg) and 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (423 mg) in1-methyl-2-pyrrolidone (3.5 mL) was stirred at 120° C. for 4 hrs. Aftercooling to room temperature, triethylamine (0.24 mL) and di-tert-butyldicarbonate (0.13 mL) were added, and the mixture was stirred for 20hrs. Water was added to the reaction system and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine and dried over magnesium sulfate. The residue wasseparated and purified by silica gel column chromatography (hexane:ethylacetate=19:1→3:2→ethyl acetate) to give a brown solid. To a solution ofthe obtained solid in tetrahydrofuran (20 mL) was added 2N hydrochloricacid (10 mL) at room temperature, and the mixture was stirred at 60° C.for 20 hrs. After concentration under reduced pressure, ethanol wasadded and the mixture was further concentrated. To the residue was addeddiisopropyl ether, and the precipitated crystals were collected byfiltration. The crystals were washed with diisopropyl ether to give thetitle compound (225 mg) as pale-yellow crystals.

¹H-NMR (DMSO-d₆) δ: 1.17 (3H, d, J=6.6 Hz), 3.35-3.77 (1H, m), 4.75-4.89(1H, m), 4.98-5.09 (1H, m), 6.75 (1H, d, J=2.7 Hz), 7.23-7.30 (2H, m),7.37 (1H, d, J=8.7 Hz), 7.52-7.54 (1H, m), 7.64-7.69 (2H, m), 7.89-7.97(1H, m), 8.04-8.10 (1H, m), 8.24-8.43 (3H, m), 8.74 (1H, s), 10.04 (1H,br s).

(iii) Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]-1-methylethyl}-2-(methylsulfonyl)acetamide

The title compound (34 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 155 (iv) using5-(2-aminopropyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (150 mg), 2-(methylsulfonyl)acetic acid (77 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (160 mg),1-hydroxybenzotriazole monohydrate (128 mg), triethylamine (0.39 mL) andN,N-dimethylformamide (5.0 mL).

¹H-NMR (CDCl₃) δ: 1.28 (3H, d, J=6.6 Hz), 3.14 (3H, s), 3.71-3.80 (1H,m), 4.00 (2H, s), 4.12-4.26 (1H, m), 4.98-5.04 (1H, m), 6.62 (1H, d,J=3.3 Hz), 6.82-6.88 (1H, m), 7.07 (1H, d, J=8.7 Hz), 7.12-7.24 (3H, m),7.30-7.35 (1H, m), 7.41-7.49 (1H, m), 7.79 (1H, dd, J=8.7, 2.7 Hz), 7.95(1H, d, J=2.7 Hz), 8.52 (1H, s), 8.54 (1H, br s).

Example 221

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxy-3-methylbutanamidemethanesulfonate

To a solution ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxy-3-methylbutanamide(200 mg) in ethyl acetate (10 mL) was added methanesulfonic acid (26 μL)at room temperature. The mixture was stirred at room temperature for 1hr and concentrated under reduced pressure. To the residue were addedethanol and ethyl acetate, and the precipitated crystals were collectedby filtration to give the title compound (223 mg) as colorless crystals.

¹H-NMR (DMSO-d₆) δ: 1.12 (6H, s), 2.21 (2H, s), 2.29 (3H, s), 3.41-3.54(2H, m), 4.56-4.68 (2H, m), 6.66 (1H, d, J=3.3 Hz), 7.26-7.28 (2H, m),7.37 (1H, d, J=9.0 Hz), 7.51-7.54 (1H, m), 7.61-7.75 (2H, m), 7.95-8.03(2H, m), 8.31-8.40 (1H, m), 8.72 (1H, s), 10.11-10.19 (1H, m).

Example 222

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-N-ethyl-2-(methylsulfonyl)acetamide(i) Production of tert-butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]ethylcarbamate

The title compound (630 mg) was obtained as a pale-yellow oil by thereaction in the same manner as in Example 163 (i) using2-(ethylamino)ethanol (1.00 g), di-tert-butyl dicarbonate (2.58 mL),tetrahydrofuran (100 mL), methanesulfonyl chloride (1.30 mL),triethylamine (3.12 mL), tetrahydrofuran (50 mL),4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.86 g), cesium carbonate (7.5 g)and N,N-dimethylformamide (20 mL).

¹H-NMR (CDCl₃) δ: 0.84-1.48 (12H, m), 2.80-2.93 (1H, m), 3.07-3.22 (1H,m), 3.51-3.67 (2H, m), 4.52-4.72 (2H, m), 6.73 (1H, d, J=3.3 Hz),7.29-7.47 (1H, m), 8.71 (1H, s).

(ii) Production of tert-butyl{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}ethylcarbamate

The title compound (950 mg) was obtained as a colorless solid by thereaction in the same manner as in Example 155 (ii) using tert-butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]ethylcarbamate (630mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (725 mg) andisopropyl alcohol (6.0 mL).

¹H-NMR (CDCl₃) δ: 1.18 (3H, t, J=7.2 Hz), 1.52 (9H, s), 3.35 (2H, q,J=7.2 Hz), 3.49-3.58 (2H, m), 4.41-4.51 (2H, m), 6.60 (1H, d, J=3.0 Hz),7.07 (1H, d, J=9.0 Hz), 7.09-7.15 (1H, m), 7.18-7.22 (2H, m), 7.29-7.33(1H, m), 7.39-7.45 (1H, m), 7.93 (1H, d, J=9.0, 2.4 Hz), 8.04 (1H, d,J=2.4 Hz), 8.51 (1H, s), 8.92 (1H, br s).

(iii) Production ofN-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-[2-(ethylamino)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride

The title compound (861 mg) was obtained as pale-yellow crystals by thereaction in the same manner as in Example 155 (iii) using tert-butyl{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}ethylcarbamate(950 mg), 2N hydrochloric acid (5.0 mL) and tetrahydrofuran (10 mL).

¹H-NMR (DMSO-d₆) δ: 1.18 (3H, t, J=7.5 Hz), 2.89-3.02 (2H, m), 3.33-3.47(2H, m), 5.03-5.12 (2H, m), 6.72-6.77 (1H, m), 7.22-7.29 (2H, m), 7.37(1H, d, J=9.0 Hz), 7.51-7.54 (1H, m), 7.61-7.71 (2H, m), 7.91-7.98 (1H,m), 8.04-8.10 (1H, m), 8.72 (1H, s), 9.05-9.21 (2H, m), 9.95-10.05 (1H,m).

(iv) Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-N-ethyl-2-(methylsulfonyl)acetamide

The title compound (94 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 155 (iv) usingN-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-[2-(ethylamino)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (150 mg), 2-(methylsulfonyl)acetic acid (76 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (158 mg),1-hydroxybenzotriazole monohydrate (126 mg), triethylamine (0.38 mL) andN,N-dimethylformamide (5.0 mL).

¹H-NMR (CDCl₃) δ: 1.36 (3H, t, J=7.2 Hz), 3.20 (3H, s), 3.61 (2H, q,J=7.2 Hz), 3.71-3.80 (2H, m), 4.15 (2H, s), 4.45-4.53 (2H, m), 6.64 (1H,d, J=3.3 Hz), 7.08 (1H, d, J=8.7 Hz), 7.10-7.17 (1H, m), 7.19-7.23 (2H,m), 7.30-7.35 (1H, m), 7.40-7.46 (1H, m), 7.89 (1H, dd, J=8.7, 2.7 Hz),7.96 (1H, d, J=2.7 Hz), 8.53 (1H, s), 8.60 (1H, s).

Example 223

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-N-ethyl-3-hydroxy-3-methylbutanamide

The title compound (106 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 155 (iv) usingN-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-[2-(ethylamino)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (150 mg), 3-hydroxy-3-methylbutyric acid (64.6 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (157 mg),1-hydroxybenzotriazole monohydrate (125 mg), triethylamine (0.38 mL) andN,N-dimethylformamide (5.0 mL).

¹H-NMR (CDCl₃) δ: 1.29 (3H, t, J=7.2 Hz), 1.34 (6H, s), 2.56 (2H, s),3.47 (2H, q, J=7.2 Hz), 3.65-3.75 (2H, m), 4.42-4.52 (3H, m), 6.62 (1H,d, J=3.0 Hz), 7.08 (1H, d, J=8.7 Hz), 7.10-7.15 (1H, m), 7.20 (1H, d,J=3.0 Hz), 7.24-7.33 (2H, m), 7.39-7.46 (1H, m), 7.72 (1H, dd, J=8.7,2.4 Hz), 8.03 (1H, d, J=2.4 Hz), 8.50 (1H, s), 8.81 (1H, s).

Example 224

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(dimethylamino)acetamide

The title compound (84 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 155 (iv) using5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (150 mg), N,N-dimethylglycine (59.4 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (166 mg),1-hydroxybenzotriazole monohydrate (132 mg), triethylamine (0.40 mL) andN,N-dimethylformamide (5.0 mL).

¹H-NMR (CDCl₃) δ: 2.29 (6H, s), 3.05 (2H, s), 3.58-3.70 (2H, m),4.45-4.54 (2H, m), 6.63 (1H, d, J=3.0 Hz), 7.08 (1H, d, J=9.0 Hz),7.10-7.15 (1H, m), 7.20 (1H, d, J=3.0 Hz), 7.23-7.34 (2H, m), 7.36-7.45(1H, m), 7.70-7.79 (2H, m), 8.10 (1H, d, J=2.7 Hz), 8.52 (1H, s), 8.63(1H, s).

Example 225

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-methyl-1,3-oxazole-4-carboxamide

The title compound (112.1 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 155 (iv) using5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (210 mg), 2-methyl-1,3-oxazole-4-carboxylic acid (210mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (560mg), 1-hydroxybenzotriazole monohydrate (100 mg), triethylamine (2.0 mL)and tetrahydrofuran (10 mL).

¹H-NMR (DMSO-d₆) δ 2.41 (3H, s), 3.56 (2H, m), 4.67 (2H, m), 6.53 (1H,d, J=3 Hz), 7.21-7.91 (8H, m), 8.30 (1H, s), 8.42 (2H, m), 8.87 (1H, brs).

Example 226

Production ofN-(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)-2,2,2-trifluoroethanesulfonamide(i) Production of2-(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)-1H-isoindole-1,3(2H)-dione

The title compound (5.20 g) was obtained by the reaction in the samemanner as in Example 172 (i) using2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol(4.00 g), tetrahydrofuran (25 mL), triethylamine (13.0 mL),methanesulfonyl chloride (7.25 mL), potassium phthalimide (4.51 g),tetrahydrofuran (60 mL) and N,N-dimethylformamide (50 mL).

¹H-NMR (DMSO-d₆) δ 3.69 (4H, s), 3.83 (2H, m), 4.61 (2H, m), 6.33 (1H,m), 7.13-7.23 (3H, m), 7.42-7.95 (9H, m), 8.24 (1H, s), 8.75 (1H, s).

(ii) Production ofN-(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)-2,2,2-trifluoroethanesulfonamide

2-(2-{2-[4-({3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)-1H-isoindole-1,3(2H)-dione(100 mg) was dissolved in ethanol (2.0 mL), hydrazine monohydrate (0.45mL) was added, and the mixture was stirred for 1 hr. To the reactionmixture was added saturated aqueous sodium hydrogen carbonate underice-cooling, and the mixture was extracted with ethyl acetate. Theextract was dried over magnesium sulfate and concentrated, and theresidue was separated and purified by basic silica gel columnchromatography (eluent, ethyl acetate:methanol=100:0→ethylacetate:methanol=95:5). The obtained oil was dissolved intetrahydrofuran (5.0 mL). N-Methylmorpholine (2.0 mL) was added,2,2,2-trifluoroethanesulfonyl chloride (0.10 mL) was added dropwiseunder ice-cooling, and the mixture was stirred for 1 hr. Underice-cooling, saturated aqueous sodium hydrogen carbonate was added, andthe mixture was extracted with dichloromethane. The extract was driedover magnesium sulfate and concentrated, and the residue was separatedand purified by silica gel column chromatography (eluent, ethylacetate:methanol=100:0→ethyl acetate:methanol=80:20). Crystallizationfrom diethyl ether/ethyl acetate gave the title compound (36.0 mg) ascrystals.

¹H-NMR (DMSO-d₆) δ 3.10 (2H, m), 3.47 (2H, m), 3.79 (2H, m), 4.30 (2H,m), 4.68 (2H, m), 6.52 (1H, m), 7.20-8.02 (9H, m), 8.35 (1H, s), 8.79(1H, s).

Example 227

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}acetamide

The title compound (62.1 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 155 (iv) using5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (270 mg), acetic acid (0.20 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (500 mg),1-hydroxybenzotriazole monohydrate (100 mg), triethylamine (2.0 mL) andtetrahydrofuran (10 mL).

¹H-NMR (DMSO-d₆) δ 1.79 (3H, s), 3.37 (2H, m), 4.51 (2H, m), 6.51 (1H,d, J=3 Hz), 7.20-7.81 (7H, m), 8.06 (1H, m), 8.26 (1H, m), 8.34 (1H, s),8.81 (1H, s).

Example 228

Production ofN-(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)-2-(methylsulfonyl)acetamidehydrochloride

2-(2-{2-[4-({3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)-1H-isoindole-1,3(2H)-dione(600 mg) was dissolved in ethanol (30 mL), hydrazine monohydrate (8.0mL) was added, and the mixture was stirred for 1 hr. To the reactionmixture was added saturated aqueous sodium hydrogen carbonate underice-cooling and the mixture was extracted with ethyl acetate. Theextract was dried over magnesium sulfate and concentrated, and theresidue was separated and purified by basic silica gel columnchromatography (eluent, ethyl acetate:methanol=100:0→ethylacetate:methanol=95:5). The title compound (312 mg) was obtained ascolorless crystals by the reaction in the same manner as in Example 155(iv) using the obtained oil, 2-(methylsulfonyl)acetic acid (500 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.50 g),1-hydroxybenzotriazole monohydrate (200 mg), triethylamine (2.0 mL) andtetrahydrofuran (20 mL).

¹H-NMR (DMSO-d₆) δ 3.06 (3H, s), 3.16-3.47 (4H, m), 3.81 (2H, m), 3.98(2H, s), 4.86 (2H, s), 6.70 (1H, m), 7.25-7.68 (6H, m), 7.97-8.01 (2H,m), 8.44 (1H, m), 8.75 (1H, s), 9.90 (1H, s).

Example 229

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-1H-pyrazole-3-carboxamide

The title compound (67.0 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 155 (iv) using5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (250 mg), 1H-pyrazole-3-carboxylic acid (210 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (500 mg),1-hydroxybenzotriazole monohydrate (100 mg), triethylamine (2.0 mL) andtetrahydrofuran (15 mL).

¹H-NMR (DMSO-d₆) δ 3.58 (2H, m), 4.64 (2H, m), 6.49 (1H, m), 6.57 (1H,s), 7.21-7.79 (8H, m), 8.01 (1H, s), 8.33 (1H, s), 8.49 (1H, m), 8.77(1H, s), 13.25 (1H, s).

Example 230

Production of(2R)—N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2,3-dihydroxypropanamide

The title compound (197.3 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 155 (iv) using5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (350 mg), (2R)-2,3-dihydroxypropanoic acid (400 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.70 g),1-hydroxybenzotriazole monohydrate (1.0 g), triethylamine (2.0 mL) andtetrahydrofuran (10 mL).

¹H-NMR (DMSO-d₆) δ 3.33-3.58 (4H, m), 3.87 (1H, m), 4.53 (2H, m), 4.69(1H, m), 5.62 (1H, d, J=5 Hz), 6.48 (1H, d, J=3 Hz), 7.20-7.81 (7H, m),8.05 (1H, d, J=2 Hz), 8.14 (1H, m), 8.34 (1H, s), 8.77 (1H, s).

Example 231

Production ofN-(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)methanesulfonamide

The title compound (18.2 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 226 (ii) using2-(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)-1H-isoindole-1,3(2H)-dione(200 mg), hydrazine monohydrate (1.50 mL), methanesulfonyl chloride(0.70 mL), N-methylmorpholine (1.20 mL), ethanol (7.0 mL) andtetrahydrofuran (10 mL).

¹H-NMR (DMSO-d₆) δ 2.78 (3H, s), 3.04 (2H, m), 3.48 (2H, m), 3.79 (2H,m), 4.68 (2H, m), 6.52 (1H, d, J=3 Hz), 7.03-7.70 (8H, m), 8.02 (1H, s),8.35 (1H, s), 8.81 (1H, s).

Example 232

Production ofN-(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)acetamide

2-(2-{2-[4-({3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)-1H-isoindole-1,3(2H)-dione(200 mg) was dissolved in ethanol (5.0 mL), hydrazine monohydrate (3.0mL) was added, and the mixture was stirred for 1 hr. To the reactionmixture was added saturated aqueous sodium hydrogen carbonate underice-cooling and the mixture was extracted with ethyl acetate. Theextract was dried over magnesium sulfate and concentrated, and theresidue was separated and purified by basic silica gel columnchromatography (eluent, ethyl acetate:methanol=100:0→ethylacetate:methanol=95:5). The title compound (146.0 mg) was obtained ascolorless crystals by the reaction in the same manner as in Example 180using the obtained oil, acetic anhydride (1.0 mL), N-methylmorpholine(1.0 mL) and tetrahydrofuran (5.0 mL).

¹H-NMR (DMSO-d₆) δ 1.69 (3H, s), 3.12 (2H, m), 3.44 (2H, m), 3.79 (2H,m), 4.66 (2H, m), 6.52 (1H, d, J=3 Hz), 7.20-7.78 (8H, m), 8.00 (1H, s),8.36 (1H, s), 8.85 (1H, s).

Example 233

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-N2-(methylsulfonyl)glycinamide

Using5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (450 mg), N-(tert-butoxy carbonyl)glycine (500 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (960 mg),1-hydroxybenzotriazole monohydrate (300 mg), triethylamine (4.0 mL) andtetrahydrofuran (25 mL), the reaction was performed in the same manneras in Example 155 (iv). The obtained compound was dissolved in methanol(5.0 mL), 4N hydrochloric acid/ethyl acetate (8 mL) was added, and themixture was stirred for 5 hrs. 8N Aqueous sodium hydroxide solution (8mL) and water (10 mL) were added and the mixture was extracted withdichloromethane. The extract was dried over magnesium sulfate andconcentrated, and the residue was dissolved in tetrahydrofuran (5.0 mL).N-Methylmorpholine (1.0 mL) was added, methanesulfonyl chloride (0.70mL) was added dropwise under ice-cooling, and the mixture was stirredfor 1 hr. Under ice-cooling, saturated aqueous sodium hydrogen carbonatewas added and the mixture was extracted with dichloromethane. Theextract was dried over magnesium sulfate and concentrated, and theresidue was separated and purified by silica gel column chromatography(eluent, ethyl acetate:methanol=100:0→ethyl acetate:methanol=80:20), andcrystallized from diethyl ether/ethyl acetate to give the title compound(47.9 mg) as crystals.

¹H-NMR (DMSO-d₆) δ 2.89 (3H, s), 3.46 (2H, m), 3.58 (2H, m), 4.54 (2H,m), 6.51 (1H, d, J=3 Hz), 7.20-7.78 (8H, m), 8.02 (1H, s), 8.27 (1H, m),8.36 (1H, s), 8.77 (1H, s).

Example 234

Production of tert-butyl4-(2-chloro-4-{[5-(2-{[(methylsulfonyl)acetyl]amino}ethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl]amino}phenoxy)piperidine-1-carboxylate(i) Production ofN-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-2-(methylsulfonyl)acetamide

tert-Butyl [2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate(300 mg) was dissolved in trifluoroacetic acid (5.0 mL), and the mixturewas stirred for 15 min. Toluene (5 mL) was added, the solvent wasevaporated, and the residue was separated and purified by basic silicagel column chromatography (eluent, ethyl acetate:methanol=100:0→ethylacetate:methanol=75:25). The title compound (64.0 mg) as colorlesscrystals were obtained by the reaction in the same manner as in Example155 (iv) using obtained oil,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.50 g),triethylamine (2.0 mL), 2-(methylsulfonyl)acetic acid (180 mg) andtetrahydrofuran (10 mL).

¹H-NMR (DMSO-d₆) δ 3.07 (3H, s), 3.57 (2H, m), 4.00 (2H, s), 4.57 (2H,m), 6.74 (1H, d, J=3 Hz), 7.92 (1H, d, J=3 Hz), 8.49 (1H, m), 8.63 (1H,s).

(ii) Production of tert-butyl4-(2-chloro-4-{[5-(2-{[(methylsulfonyl)acetyl]amino}ethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl]amino}phenoxy)piperidine-1-carboxylate

The title compound (24.0 mg) was obtained as colorless crystals by thereaction in the same manner as in Example 155 (ii) usingN-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-2-(methylsulfonyl)acetamide(60.0 mg) and tert-butyl4-(4-amino-2-chlorophenoxy)piperidine-1-carboxylate (160 mg).

¹H-NMR (DMSO-d₆) δ 1.41 (9H, s), 1.50-1.70 (2H, m), 1.81-1.95 (2H, m),3.10 (3H, s), 3.22-3.60 (6H, m), 4.04 (2H, s), 4.45-4.65 (3H, m), 6.47(1H, d, J=3 Hz), 7.23 (1H, d, J=9 Hz), 7.55-7.58 (2H, m), 7.75 (1H, d,J=3 Hz), 8.27 (1H, s), 8.48 (1H, s), 8.66 (1H, m).

Example 235

Production of3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]-N-[2-(methylsulfonyl)ethyl]propanamidehydrochloride (i) Production of ethyl3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propanoate

4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (303 mg) was dissolved inN,N-dimethylformamide (9 mL), ethyl acrylate (0.3 mL) and potassiumcarbonate (538 mg) were sequentially added, and the mixture was stirredat room temperature for 7.5 hrs. Ethyl acrylate (0.2 mL) was added, andthe mixture was stirred for 16 hrs. Ethyl acrylate (0.3 mL) andpotassium carbonate (526 mg) were further added, and the mixture wasstirred for 6 hrs. The reaction mixture was treated with saturatedaqueous ammonium chloride solution and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was separated and purified by silica gel columnchromatography (eluent, hexane:ethyl acetate=66:34→20:80) to give thetitle compound (404 mg) as a colorless oil.

¹H-NMR (CDCl₃) δ: 1.22 (3H, t, J=7.1 Hz), 2.92 (2H, t, J=6.3 Hz), 4.13(2H, q, J=7.1 Hz), 4.80 (2H, t, J=6.3 Hz), 6.70 (1H, d, J=3.3 Hz), 7.61(1H, d, J=3.3 Hz), 8.71 (1H, s).

(ii) Production of ethyl3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propanoate

The title compound (687 mg) was obtained as a pale-yellow oil by thereaction in the same manner as in Example 201 (iii) using ethyl3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propanoate (404 mg),isopropyl alcohol (10 mL) and3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (555 mg).

¹H-NMR (CDCl₃) δ: 1.26 (3H, t, J=7 Hz), 2.99-3.10 (2H, m), 4.24 (2H, q,J=7 Hz), 4.53-4.65 (2H, m), 6.69 (1H, d, J=3.3 Hz), 7.06-7.17 (2H, m),7.18-7.24 (1H, m), 7.27-7.35 (2H, m), 7.43 (1H, t, J=7.9 Hz), 7.65 (1H,dd, J=8.8 Hz, 2.6 Hz), 7.92 (1H, d, J=2.6 Hz), 8.54 (1H, s), 9.14 (1H,s).

(iii) Production of3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propanoicacid

The title compound (595 mg) was obtained as a pale-yellow powder by thereaction in the same manner as in Example 202 (ii) using a mixed solventof ethyl3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propanoate(683 mg), 1N aqueous sodium hydroxide solution (2 mL) andtetrahydrofuran (6 mL)/ethanol (6 mL).

¹H-NMR (DMSO-d₆) δ: 2.84 (2H, t, J=6.4 Hz), 4.69 (2H, t, J=6.4 Hz), 6.52(1H, d, J=3.0 Hz), 7.14-7.29 (2H, m), 7.32 (1H, d, J=8.9 Hz), 7.47 (1H,d, J=7.7 Hz), 7.56-7.80 (3H, m) 7.94 (1H, s), 8.35 (1H, s), 9.10 (1H,s), 12.72 (1H, s)

(iv) Production of3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]-N-[2-(methylsulfonyl)ethyl]propanamidehydrochloride

3-[4-({3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]-N-[2-(methylsulfonyl)ethyl]propanamide(140 mg) was obtained by the reaction in the same manner as in Example202 (iii) using3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propanoicacid (199 mg), 2-(methylsulfonyl)ethanamine (106 mg),1-hydroxybenzotriazole monohydrate (84.7 mg),N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (128.6mg), triethylamine (0.1 mL) and N,N-dimethylformamide (2 mL). Theobtained3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]-N-[2-(methylsulfonyl)ethyl]propanamidewas dissolved in ethyl acetate (2 mL), 4N hydrochloric acid-ethylacetate (0.1 mL) was added, and the precipitate was collected byfiltration and dried to give the title compound (119 mg) as a whitepowder.

¹H-NMR (DMSO-d₆) δ: 2.82-2.90 (2H, m), 2.91 (3H, s), 3.18 (2H, t, J=6.6Hz), 3.40-3.51 (2H, m), 4.72-4.83 (2H, m), 6.70 (1H, d, J=3.0 Hz),7.23-7.32 (2H, m), 7.41 (1H, d, J=8.8 Hz), 7.52 (1H, d, J=7.7 Hz), 7.66(1H, t, J=7.7 Hz), 7.74 (1H, dd, J=8.8 Hz, 2.5 Hz), 8.01-8.08 (2H, m),8.67 (1H, t, J=5.6 Hz), 8.76 (1H, s), 10.80 (1H, s).

Example 236

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxypropanamidehydrochloride

N-{2-[4-({3-Chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxypropanamidewas obtained by the reaction in the same manner as in Example 202 (iii)using5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (303 mg), 3.6M aqueous solution (0.25 mL) of3-hydroxypropanoic acid, 1-hydroxybenzotriazole monohydrate (231 mg),N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (322 mg),triethylamine (0.8 mL) and N,N-dimethylformamide (3 mL). The obtainedN-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxypropanamidewas dissolved in ethyl acetate (2 mL), 4N hydrochloric acid-ethylacetate (0.1 mL) was added, and the obtained product was crystallizedfrom ethyl acetate to give the title compound (80.9 mg) as whitecrystals.

¹H-NMR (DMSO-d₆) δ: 2.21 (2H, t, J=6.5 Hz), 3.39-3.51 (2H, m), 3.54 (2H,t, J=6.5 Hz), 4.67 (2H, t, J=7.0 Hz), 6.68 (1H, t, J=3.0 Hz), 6.94-7.04(2H, m), 7.16 (1H, d, J=8.3 Hz), 7.36 (1H, d, J=8.8 Hz), 7.54 (1H, t,J=8.3 Hz), 7.72 (1H, dd, J=8.8 Hz, 2.6 Hz), 7.93-8.04 (2H, m), 8.36 (1H,t, J=5.8 Hz), 8.74 (1H, s), 10.23 (1H, s).

Example 237

Production of5-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]pentane-1,2-diol(i) Production of 3-(2,2-dimethyl-1,3-dioxolan-4-yl)propan-1-ol

Pentane-1,2,5-triol (5.00 g) was dissolved in acetone (150 mL),2,2-dimethoxypropane (10.5 mL) and 4-methylbenzenesulfonic acid (794 mg)were added, and the mixture was stirred at room temperature for 1.5 hrs.The reaction mixture was concentrated under reduced pressure, and theresidue was separated and purified by silica gel column chromatography(eluent, hexane:ethyl acetate=80:20→50:50) to give the title compound(3.79 g) as a colorless oil.

¹H-NMR (CDCl₃) δ: 1.37 (3H, s), 1.42 (3H, s), 1.57-1.77 (4H, m), 2.05(1H, br s), 3.53 (1H, t, J=7.3 Hz), 3.60-3.77 (2H, m), 4.00-4.21 (2H,m).

(ii) Production of 3-(2,2-dimethyl-1,3-dioxolan-4-yl)propylmethanesulfonate

The title compound (2.13 g) was obtained as a colorless oil by thereaction in the same manner as in Example 203 (ii) using3-(2,2-dimethyl-1,3-dioxolan-4-yl)propan-1-ol (2.30 g), methanesulfonylchloride (0.8 mL), triethylamine (3.0 mL) and ethyl acetate (50 mL).

¹H-NMR (CDCl₃) δ: 1.35 (3H, s), 1.41 (3H, s), 1.62-1.73 (2H, m),1.75-2.02 (2H, m), 3.02 (3H, m), 3.50-3.57 (1H, m), 4.02-4.17 (2H, m),4.21-4.36 (2H, m).

(iii) Production of4-chloro-5-[3-(2,2-dimethyl-1,3-dioxolan-4-yl)propyl]-5H-pyrrolo[3,2-d]pyrimidine

The title compound (176 mg) was obtained as a white powder by thereaction in the same manner as in Example 201 (ii) using4-chloro-5H-pyrrolo[3,2-d]pyrimidine (151 mg),3-(2,2-dimethyl-1,3-dioxolan-4-yl)propyl methanesulfonate (319 mg),cesium carbonate (574 mg) and N,N-dimethylformamide (1.5 mL).

¹H-NMR (CDCl₃) δ: 1.34 (3H, s), 1.40 (3H, s), 1.53-1.73 (2H, m)1.80-2.13 (2H, m), 3.47-3.53 (1H, m), 3.97-4.18 (2H, m), 4.41-4.70 (2H,m), 6.72 (1H, d, J=3.3 Hz), 7.51 (1H, d, J=3.3 Hz), 8.70 (1H, s).

(iv) Production of5-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]pentane-1,2-diol

The crude product was obtained by the reaction in the same manner as inExample 201 (iii) using4-chloro-5-[3-(2,2-dimethyl-1,3-dioxolan-4-yl)propyl]-5H-pyrrolo[3,2-d]pyrimidine(171 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (195 mg) andisopropyl alcohol (3.5 mL). The crude product was dissolved in methanol(1 mL), 1N hydrochloric acid (0.5 mL) was added, and the mixture wasstirred at room temperature for 3.5 hrs. The reaction mixture wastreated with 1N aqueous sodium hydroxide solution, extracted with ethylacetate, washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue wasseparated and purified by silica gel column chromatography (eluent,ethyl acetate:methanol=100:0→95:5) to give the title compound (179 mg)as white crystals.

¹H-NMR (DMSO-d₆) δ: 1.03-1.41 (2H, m), 1.61-1.93 (2H, m), 3.08-3.28 (2H,m), 3.28-3.43 (1H, m), 4.44 (1H, t, J=5.5 Hz), 4.47-4.59 (3H, m), 6.49(1H, d, J=3.0 Hz), 7.17-7.27 (2H, m), 7.30 (1H, d, J=9.1 Hz), 7.47 (1H,d, J=8.5 Hz), 7.57-7.74 (3H, m), 7.97 (1H, d, J=2.4 Hz), 8.34 (1H, s),8.61 (1H, s).

Example 238

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxypropanamidehydrochloride

N-{2-[4-({3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxypropanamidewas obtained by the reaction in the same manner as in Example 202 (iii)using5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (300 mg), 3.6 M aqueous solution (0.25 mL) of3-hydroxypropanoic acid, 1-hydroxybenzotriazole monohydrate (231 mg),N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (330 mg),triethylamine (0.8 mL) and N,N-dimethylformamide (3 mL). The obtainedN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxypropanamidewas dissolved in ethyl acetate (2 mL), and 4N hydrochloric acid-ethylacetate (0.1 mL) was added. The obtained product was recrystallized fromethyl acetate to give the title compound (63.1 mg) as a white powder.

¹H-NMR (DMSO-d₆) δ: 2.22 (2H, t, J=6.5 Hz), 3.39-3.52 (2H, m), 3.55 (2H,t, J=6.5 Hz), 4.65 (2H, t, J=6.7 Hz), 6.67 (1H, d, J=3.0 Hz), 7.24-7.32(2H, m), 7.37 (1H, d, J=8.8 Hz), 7.53 (1H, d, J=8.0 Hz), 7.66 (1H, t,J=8.0 Hz), 7.72 (1H, dd, J=8.8 Hz, 2.5 Hz), 7.96-8.01 (2H, m), 8.34 (1H,t, J=5.8 Hz), 8.74 (1H, s), 10.17 (1H, s).

Example 239

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3,3,3-trifluoropropanamide

The title compound (64.0 mg) was obtained as yellow crystals by thereaction in the same manner as in Example 202 (iii) using5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (150 mg), 3,3,3-trifluoropropanoic acid (0.06 mL),1-hydroxybenzotriazole monohydrate (142 mg),N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (200 mg),triethylamine (0.4 mL) and N,N-dimethylformamide (1.5 mL) andcrystallization from diisopropyl ether.

¹H-NMR (DMSO-d₆) δ: 3.19 (2H, q, J=11.2 Hz) 3.43 (2H, m), 4.58 (2H, t,J=6.4 Hz), 6.52 (1H, d, J=3.0 Hz), 7.18-7.26 (2H, m), 7.30 (1H, d, J=9Hz), 7.47 (1H, d, J=7.5 Hz), 7.57-7.67 (2H, m), 7.76 (1H, dd, J=9 Hz,2.5 Hz), 8.00 (1H, d, J=2.5 Hz), 8.36 (1H, s), 8.50 (1H, t, J=5.3 Hz),8.72 (1H, s).

Example 240

Production of3-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}propane-1,2-diolhydrochloride (i) Production of tert-butyl{2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethoxy}dimethylsilane

60% Sodium hydride (890 mg) was suspended in N,N-dimethylformamide (60mL), and the suspension was cooled to 0° C.(2,2-Dimethyl-1,3-dioxolan-4-yl)methanol (2.3 mL) was added dropwise andthe mixture was stirred at 0° C. for 1 hr. To the reaction mixture wasadded (2-bromoethoxy)(tert-butyl)dimethylsilane (3 mL), and the mixturewas stirred at 0° C. for 2 hrs. To the reaction mixture was addedsaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was separated and purified by silicagel column chromatography (eluent, hexane:ethyl acetate=100:0→90:10) togive the title compound (1.04 g) as a yellow oil.

¹H-NMR (CDCl₃) δ: 0.06 (6H, s), 0.89 (9H, s), 1.36 (3H, s), 1.42 (3H,s), 3.47-3.63 (4H, m) 3.71-3.79 (3H, m), 4.06 (1H, dd, J=8.2 Hz, 6.3Hz), 4.20-4.35 (1H, m).

(ii) Production of 2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethylmethanesulfonate

tert-Butyl{2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethoxy}dimethylsilane(1.03 g) was dissolved in tetrahydrofuran (20 mL), a 1.0 M solution (4mL) of tetrabutylammonium fluoride in tetrahydrofuran was added, and themixture was stirred at room temperature for 1 hr. To the reactionmixture was added saturated aqueous ammonium chloride solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved in ethylacetate (20 mL) and subjected the reaction similar to that in Example203 (ii) using methanesulfonyl chloride (0.3 mL) and triethylamine (2mL) to give the title compound (857 mg) as a yellow oil.

¹H-NMR (CDCl₃) δ: 1.36 (3H, s), 1.42 (3H, s), 3.07 (3H, s), 3.56 (1H, d,J=1.4 Hz), 3.58 (1H, d, J=1.9 Hz), 3.73 (1H, dd, J=8.3 Hz, 6.3 Hz),3.77-3.82 (2H, m), 4.06 (1H, dd, J=8.3 Hz, 6.3 Hz), 4.24-4.33 (1H, m),4.35-4.41 (2H, m).

(iii) Production of4-chloro-5-{2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidine

The title compound (298 mg) was obtained as a colorless oil by thereaction in the same manner as in Example 201 (ii) using4-chloro-5H-pyrrolo[3,2-d]pyrimidine (152 mg),2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethyl methanesulfonate (327mg), cesium carbonate (576 mg) and N,N-dimethylformamide (1.5 mL).

¹H-NMR (CDCl₃) δ: 1.33 (3H, s), 1.38 (3H, s), 3.37-3.50 (2H, m), 3.59(1H, dd, J=8.3 Hz, 6.6 Hz), 3.87 (2H, dt, J=5.1 Hz, 2.2 Hz), 3.96 (1H,dd, J=8.3 Hz, 6.6 Hz), 4.11-4.22 (1H, m), 4.66-4.72 (2H, m), 6.71 (1H,d, J=3 Hz), 7.57 (1H, d, J=3 Hz), 8.70 (1H, s).

(iv) Production of3-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}propane-1,2-diolhydrochloride

3-{2-[4-({3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}propane-1,2-diolwas obtained by the reaction in the same manner as in Example 237 (iv)using4-chloro-5-{2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidine(295 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (359 mg) andisopropyl alcohol (6 mL). The obtained3-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-O]pyrimidin-5-yl]ethoxy}propane-1,2-diolwas dissolved in ethyl acetate (6 mL), 4N hydrochloric acid-ethylacetate (0.2 mL) was added, and the mixture was concentrated underreduced pressure. The residue was crystallized from ethyl acetate togive the title compound (360 mg) as a white powder.

¹H-NMR (DMSO-d₆) δ: 3.10-3.26 (2H, m), 3.31-3.42 (1H, m), 3.42-3.56 (2H,m), 3.78-3.89 (2H, m), 4.77-4.89 (2H, m), 6.71 (1H, d, J=3.0 Hz),7.22-7.31 (2H, m), 7.36 (1H, d, J=8.8 Hz), 7.52 (1H, d, J=7.7 Hz),7.60-7.73 (2H, m), 7.96-8.06 (2H, m), 8.75 (1H, s), 9.96 (1H, s).

Example 241

Production ofN-[2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl]amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-cyanoacetamide

The title compound (104 mg) was obtained as a yellow powder by thereaction in the same manner as in Example 202 (iii) using5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (201 mg), cyanoacetic acid (65.9 mg),1-hydroxybenzotriazole monohydrate (215 mg),N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (300 mg),triethylamine (0.55 mL) and N,N-dimethylformamide (2.0 mL) andcrystallization from diisopropyl ether.

¹H-NMR (DMSO-d₆) δ: 3.36-3.47 (2H, m), 3.56 (2H, s), 4.58 (2H, t, J=6.3Hz), 6.52 (1H, d, J=3.3 Hz), 7.18-7.28 (2H, m), 7.31 (1H, d, J=8.8 Hz),7.47 (1H, d, J=7.7 Hz), 7.56-7.68 (2H, m), 7.73 (1H, dd, J=8.8 Hz, 2.5Hz), 7.99 (1H, d, J=2.5 Hz), 8.36 (1H, s), 8.44 (1H, t, J=5.8 Hz), 8.67(1H, s).

Example 242

Production ofN-{4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]but-2-yn-1-yl}-2-(methylsulfonyl)acetamide(i) Production of tert-butyl (4-chlorobut-2-yn-1-yl)carbamate

4-Chlorobut-2-yn-1-amine hydrochloride (10.5 g) was dissolved in a mixedsolvent of water (200 mL)/methanol (40 mL), di-tert-butyl dicarbonate(19 mL) was added, and the mixture was stirred at room temperature for 2hrs. In this case, the reaction solution was maintained at pH 10-11 with4N aqueous sodium hydroxide solution. Water was added to the reactionmixture and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue wasseparated and purified by silica gel column chromatography (eluent,hexane:ethyl acetate=100:0→80:20) to give the title compound (14.5 g) asa pale-yellow oil.

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 3.89-4.06 (2H, m), 4.14 (2H, t, J=2.1Hz), 4.71 (1H, br s).

(ii) Production of tert-butyl[4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)but-2-yn-1-yl]carbamate

A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.51 g), tert-butyl(4-chlorobut-2-yn-1-yl)carbamate (2.60 g), cesium carbonate (4.80 g) andN,N-dimethylformamide (15 mL) was stirred at room temperature for 2 hrs.Water was added to the reaction mixture and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was separated and purified by silica gel columnchromatography (eluent, hexane:ethyl acetate=80:20→33:67) to give thetitle compound (2.61 g) as an orange oil.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 3.87-4.05 (2H, m), 4.71 (1H, s), 5.29(2H, t, J=2.1 Hz), 6.76 (1H, d, J=3.3 Hz), 7.70 (1H, d, J=3.3 Hz), 8.72(1H, s).

(iii) Production of tert-butyl{4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]but-2-yn-1-yl}carbamate

The title compound (1.86 g) was obtained as a colorless powder by thereaction in the same manner as in Example 201 (iii) using tert-butyl[4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)but-2-yn-1-yl]carbamate(1.32 g), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (1.43 g) andisopropyl alcohol (25 mL) and crystallization from hexane/diisopropylether.

¹H-NMR (CDCl₃) δ: 1.39 (9H, s), 4.03-4.08 (2H, m), 4.80 (1H, br s), 5.08(2H, t, J=2.1 Hz), 6.60 (1H, d, J=3.3 Hz), 7.09 (1H, d, J=8.8 Hz),7.10-7.15 (1H, m), 7.18-7.23 (2H, m), 7.33 (1H, d, J=7.8 Hz), 7.43 (1H,t, J=7.8 Hz), 7.51 (1H, dd, J=8.8 Hz, 2.5 Hz), 7.68 (1H, s), 7.97 (1H,d, J=2.5 Hz), 8.56 (1H, s).

(iv) Production of5-(4-aminobut-2-yn-1-yl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride

tert-Butyl{4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]but-2-yn-1-yl}carbamate(1.90 g) was dissolved in tetrahydrofuran (35 mL), 2N hydrochloric acid(18 mL) was added, and the mixture was stirred at 60° C. for 16 hrs. Tothe reaction mixture was added ethanol, and the mixture was concentratedunder reduced pressure. The residue was crystallized from ethyl acetateto give the title compound (802 mg) as a white powder.

¹H-NMR (DMSO-d₆) δ: 3.71-3.84 (2H, m), 5.97 (2H, s), 6.74 (1H, d, J=3Hz), 7.23-7.32 (2H, m), 7.36 (1H, d, J=8.8 Hz), 7.52 (1H, d, J=8.0 Hz),7.66 (1H, t, J=8.0 Hz), 7.76 (1H, dd, J=8.8 Hz, 2.5 Hz), 8.05 (1H, d,J=2.5 Hz), 8.21 (1H, d, J=3 Hz), 8.42-8.60 (3H, m), 8.76 (1H, s), 10.49(1H, s).

(v) Production ofN-{4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]but-2-yn-1-yl}-2-(methylsulfonyl)acetamide

The title compound (55.8 mg) was obtained as a pale-yellow powder by thereaction in the same manner as in Example 202 (iii) using5-(4-aminobut-2-yn-1-yl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (204 mg), methanesulfonylacetic acid (102 mg),1-hydroxybenzotriazole monohydrate (204 mg),N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (287 mg),triethylamine (0.5 mL) and N,N-dimethylformamide (2 mL) andcrystallization from diisopropyl ether/ethyl acetate.

¹H-NMR (DMSO-d₆) δ: 3.07 (3H, s), 3.92-4.00 (2H, m), 4.02 (2H, s), 5.50(2H, s), 6.55 (1H, d, J=3 Hz), 7.18-7.28 (2H, m), 7.32 (1H, d, J=9.1Hz), 7.48 (1H, d, J=7.1 Hz), 7.57-7.70 (2H, m), 7.76 (1H, d, J=3 Hz),8.02 (1H, d, J=2.5 Hz), 8.39 (1H, s), 8.62 (1H, s), 8.77 (1H, t, J=5.5Hz).

Example 243

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide

The title compound (104 mg) was obtained as white crystals by thereaction in the same manner as in Example 202 (iii) using5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (201 mg), 4,4,4-trifluoro-3-hydroxy-3-methylbutanoicacid (131 mg), 1-hydroxybenzotriazole monohydrate (159 mg),N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (372 mg),triethylamine (0.55 mL) and tetrahydrofuran (2 mL) and crystallizationfrom diisopropyl ether/ethyl acetate.

¹H-NMR (DMSO-d₆) δ: 1.36 (3H, s), 2.26-2.48 (2H, m), 3.36-3.56 (2H, m),4.53 (2H, t, J=6.7 Hz), 6.18 (1H, s), 6.51 (1H, d, J=3.0 Hz), 7.15-7.26(2H, m), 7.30 (1H, d, J=8.8 Hz), 7.47 (1H, d, J=8.0 Hz), 7.56-7.72 (2H,m), 7.81 (1H, dd, J=8.8 Hz, 2.5 Hz), 8.04 (1H, d, J=2.5 Hz), 8.35 (1H,s), 8.42 (1H, t, J=5.9 Hz), 8.83 (1H, s).

Example 244

Production of4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]butanoicacid (i) Production of ethyl4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)butanoate

The title compound (1.70 g) was obtained as a yellow oil by the reactionin the same manner as in Example 201 (ii) using4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.01 g), ethyl 4-bromobutanoate(1.2 mL), cesium carbonate (3.23 g) and N,N-dimethylfonmamide (10 mL).

¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7 Hz), 2.09-2.44 (4H, m), 4.13 (2H, q,J=7 Hz), 4.56 (2H, t, J=7.0 Hz), 6.73 (1H, d, J=3 Hz), 7.50 (1H, d, J=3Hz), 8.71 (1H, s).

(ii) Production of ethyl4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]butanoate

The title compound (2.69 g) was obtained as a yellow solid by thereaction in the same manner as in Example 201 (iii) using ethyl4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)butanoate (1.70 g),3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (2.19 g) and isopropylalcohol (35 mL).

¹H-NMR (CDCl₃) δ: 1.31 (3H, t, J=7.2 Hz), 2.12-2.27 (2H, m), 2.50-2.61(2H, m), 4.24 (2H, q, J=7.2 Hz), 4.34-4.48 (2H, m), 6.60 (1H, d, J=3.3Hz), 7.08 (1H, d, J=8.0 Hz), 7.11-7.17 (1H, m), 7.19-7.25 (2H, m), 7.32(1H, d, J=8.0 Hz), 7.43 (1H, t, J=8.0 Hz), 7.82 (1H, dd, J=8.8 Hz, 2.6Hz), 8.00 (1H, d, J=2.6 Hz), 8.16 (1H, s), 8.52 (1H, s).

(iii) Production of4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]butanoicacid

The title compound (2.02 g) was obtained as a white solid by thereaction in the same manner as in Example 202 (ii) using ethyl4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]butanoate(2.69 g), 1N aqueous sodium hydroxide solution (7 mL) and a mixedsolvent of tetrahydrofuran (20 mL)/ethanol (20 mL).

¹H-NMR (DMSO-d₆) δ: 1.87-2.00 (2H, m), 2.20 (2H, t, J=6.9 Hz), 4.52 (2H,t, J=7.6 Hz), 6.50 (1H, d, J=3.0 Hz), 7.17-7.28 (2H, m), 7.30 (1H, d,J=8.8 Hz), 7.47 (1H, d, J=7.7 Hz), 7.57-7.76 (3H, m), 7.99 (1H, d, J=2.5Hz), 8.34 (1H, s), 8.61 (1H, s), 12.33 (1H, s).

Example 245

Production of4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]-N-[2-(methylsulfonyl)ethyl]butanamide

The title compound (142 mg) was obtained as white crystals by thereaction in the same manner as in Example 202 (iii) using4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]butanoicacid (250 mg), 2-(methylsulfonyl)ethanamine (128 mg),1-hydroxybenzotriazole monohydrate (114 mg),N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (492 mg),triethylamine (0.15 mL) and a mixed solvent of tetrahydrofuran (1.5mL)/N,N-dimethylformamide (1.5 mL) and crystallization from ethylacetate.

¹H-NMR (DMSO-d₆) δ: 1.90-2.03 (2H, m), 2.08-2.19 (2H, m), 2.97 (3H, s),3.20-3.30 (2H, m), 3.40-3.52 (2H, m), 4.49 (2H, t, J=7.2 Hz), 6.50 (1H,d, J=3 Hz), 7.17-7.24 (1H, m), 7.24-7.27 (1H, m), 7.30 (1H, d, J=9 Hz),7.47 (1H, d, J=8 Hz), 7.62 (1H, t, J=8 Hz), 7.67 (1H, d, J=3 Hz), 7.82(1H, dd, J=9 Hz, 2.5 Hz), 8.09 (1H, d, J=2.5 Hz), 8.29 (1H, t, J=5.6Hz), 8.34 (1H, s), 8.79 (1H, s).

Example 246

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxypropanamidemethanesulfonate

N-{2-[4-({3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxypropanamidewas obtained by the reaction in the same manner as in Example 202 (iii)using5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (3.50 g), a 3.6 M aqueous solution (5.6 mL) of3-hydroxypropanoic acid, 1-hydroxybenzotriazole monohydrate (4.56 g),N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (10.1 g),triethylamine (10 mL) and a mixed solvent of tetrahydrofuran (17mL)/N,N-dimethylformamide (17 mL). The obtainedN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxypropanamidewas dissolved in ethyl acetate (50 mL), methanesulfonic acid (0.155 mL)was added, and the mixture was stirred for 2 hrs. The reaction mixturewas concentrated under reduced pressure and recrystallized from ethylacetate to give the title compound (1.04 g) as white crystals.

¹H-NMR (DMSO-d₆) δ: 2.22 (2H, t, J=6.3 Hz), 2.31 (3H, s), 3.41-3.51 (4H,m), 3.56 (2H, t, J=6.5 Hz), 6.67 (1H, d, J=3.0 Hz), 7.25-7.32 (2H, m),7.37 (1H, d, J=8.8 Hz), 7.50-7.56 (1H, m), 7.62-7.74 (2H, m), 7.98 (1H,d, J=2.8 Hz), 8.33 (1H, t, J=5.5 Hz), 8.75 (1H, s), 10.11 (1H, s).

Example 247

Production of4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]-N-methoxybutanamide

The title compound (98.1 mg) was obtained as white crystals by thereaction in the same manner as in Example 202 (iii) using4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]butanoic acid (252 mg), O-methylhydroxylaminehydrochloride (85 mg), 1-hydroxybenzotriazole monohydrate (105 mg),N-[3-(dimethylamino)propy]-N-ethylcarbodiimide hydrochloride (484 mg),triethylamine (0.7 mL) and a mixed solvent of tetrahydrofuran (1mL)/N,N-dimethylformamide (1 mL).

¹H-NMR (DMSO-d₆) δ: 1.92-1.99 (4H, m), 3.55 (3H, s), 4.46-4.56 (2H, m),6.51 (1H, d, J=2.8 Hz), 7.18-7.27 (2H, m), 7.30 (1H, d, J=8.8 Hz), 7.47(1H, d, J=7.7 Hz), 7.58-7.69 (2H, m), 7.74-7.81 (1H, m), 8.03 (1H, s),8.34 (1H, s), 8.75 (1H, br s), 11.02 (1H, br s).

Example 248

Production of3-hydroxy-3-methyl-N-{2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}butanamide

The title compound (203 mg) was obtained as colorless powder crystals bythe reaction in the same manner as in Example 155 (iv) using5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine(238 mg), 3-hydroxy-3-methylbutanoic acid (0.0865 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (154 mg),1-hydroxybenzotriazole monohydrate (109 mg), triethylamine (0.374 mL)and N,N-dimethylformamide (10.5 mL).

¹H-NMR (DMSO-d₆) δ 1.13 (6H, s), 2.12 (3H, s), 2.21 (2H, s), 3.41 (2H,m), 4.51 (2H, t, J=6 Hz), 4.70 (1H, s), 6.47 (1H, d, J=3 Hz), 6.88 (2H,m), 7.04 (2H, m), 7.47 (1H, t, J=8 Hz), 7.61 (1H, d, J=3 Hz), 7.65 (2H,m), 8.28 (2H, m), 8.73 (1H, br s).

Example 249

Production of3-hydroxy-3-methyl-N-{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}butanamide(i) Production of5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride

tert-Butyl{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate(2.9 g) obtained in Example 188 (i) was dissolved in tetrahydrofuran (80mL)/2N hydrochloric acid (40 mL), and the mixture was stirred at 60° C.for 16 hrs. The reaction mixture was concentrated under reducedpressure, ethanol (80 mL) was added to the residue and the mixture wasconcentrated again under reduced pressure. Ethyl acetate was added tothe residue and the solid was collected by filtration and dried underreduced pressure to give the title compound (2.58 g) as a solid powder.

¹H-NMR (DMSO-d₆) δ 2.20 (3H, s), 3.29 (2H, m), 5.06 (2H, m), 6.73 (1H,d, J=3 Hz), 7.11 (1H, d, J=9 Hz), 7.22 (2H, m), 7.48 (2H, m), 7.61 (2H,m), 8.08 (1H, d, J=3 Hz), 8.42 (3H, br s), 8.70 (1H, s), 10.04 (1H, brs).

(ii) Production of3-hydroxy-3-methyl-N-{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}butanamide

The title compound (203 mg) was obtained as colorless powder crystals bythe reaction in the same manner as in Example 155 (iv) using5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (200 mg), 3-hydroxy-3-methylbutanoic acid (0.0644 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg),1-hydroxybenzotriazole monohydrate (81 mg), triethylamine (0.279 mL) andN,N-dimethylformamide (7.82 mL).

¹H-NMR (DMSO-d₆) δ 1.13 (6H, s), 2.13 (3H, s), 2.21 (2H, s), 3.42 (2H,m), 4.52 (2H, t, J=7 Hz), 4.69 (1H, s), 6.47 (1H, d, J=3 Hz), 7.03 (1H,m), 7.18 (2H, m), 7.42 (1H, d, J=8 Hz), 7.5-7.7 (4H, m), 8.26 (2H, m),8.73 (1H, br s).

Example 250

Production of2-{2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol

The title compound (132 mg) was obtained colorless crystals by themethod in the same manner as in Example 183 using2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate(150 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (139 mg) and1-methyl-2-pyrrolidone (0.863 mL).

¹H-NMR (DMSO-d₆) δ 2.17 (3H, s), 2.43 (3H, s), 3.51 (4H, br s), 3.84(2H, t, J=4.5 Hz), 4.63 (2H, t, J=4.5 Hz), 4.73 (1H, t, J=4.5 Hz), 6.49(1H, d, J=3 Hz), 6.93 (1H, d, J=8 Hz), 7.16 (1H, dd, J=9 Hz, 3 Hz), 7.23(1H, d, J=8 Hz), 7.56 (2H, m), 7.65 (1H, d, J=3 Hz), 8.17 (1H, d, J=3Hz), 8.28 (1H, s), 8.78 (1H, br s).

Example 251

Production ofN-{2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide(i) Production of tert-butyl{2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate

The title compound (799 mg) was obtained as a white powder by the methodin the same manner as in Example 188 (i) using tert-butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (500 mg),3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (542 mg) and isopropylalcohol (5 mL).

¹H-NMR (CDCl₃) δ 1.47 (9H, s), 2.24 (3H, s), 2.52 (3H, s), 3.49 (2H, m),4.46 (2H, m), 5.18 (1H, m), 6.58 (1H, d, J=3 Hz), 6.89 (1H, d, J=9 Hz),7.0-7.2 (3H, m), 7.65 (2H, m), 8.27 (1H, d, J=2 Hz), 8.41 (1H, br s),8.48 (1H, s).

(ii) Production of5-(2-aminoethyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminetrihydrochloride

tert-Butyl{2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate(790 mg) was dissolved in tetrahydrofuran (24 mL)/2N hydrochloric acid(12 mL), and the mixture was stirred at 60° C. for 16 hrs. The reactionmixture was concentrated under reduced pressure, ethanol (30 mL) wasadded to the residue and the mixture was concentrated again underreduced pressure. Ethyl acetate was added to the residue and the solidwas collected by filtration and dried under reduced pressure to give thetitle compound (701 mg) as a solid powder.

¹H-NMR (DMSO-d₆) δ 2.23 (3H, s), 2.68 (3H, s), 3.29 (2H, m), 5.11 (2H,m), 6.74 (1H, d, J=3 Hz), 7.16 (1H, d, J=8 Hz), 7.52 (1H, d, J=9 Hz),7.62 (1H, s), 7.80 (1H, m), 7.96 (1H, m), 8.10 (1H, m), 8.37 (1H, d, J=3Hz), 8.51 (3H, br s), 8.71 (1H, s).

(iii) Production ofN-{2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide

The title compound (205 mg) was obtained as colorless powder crystals bythe reaction in the same manner as in Example 155 (iv) using5-(2-aminoethyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminetrihydrochloride (250 mg), 2-(methylsulfonyl)acetic acid (107 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (149 mg),1-hydroxybenzotriazole monohydrate (105 mg), triethylamine (0.360 mL)and N,N-dimethylformamide (10 mL).

¹H-NMR (DMSO-d₆) δ 2.17 (3H, s), 2.44 (3H, s), 3.34 (3H, s), 3.45 (2H,q, J=6 Hz), 4.05 (2H, s), 4.55 (2H, t, J=6 Hz), 6.47 (1H, d, J=3 Hz),6.94 (1H, d, J=9 Hz), 7.1-7.3 (2H, m), 7.55 (3H, m), 8.18 (1H, d, J=3Hz), 8.28 (1H, s), 8.51 (1H, br s), 8.67 (1H, t, J=5 Hz).

Example 252

Production of2-[2-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethanol

The title compound (149 mg) was obtained as colorless crystals by themethod in the same manner as in Example 183 using2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate(150 mg), 3-chloro-4-(pyridin-2-ylmethoxy)aniline (152 mg) and1-methyl-2-pyrrolidone (0.863 mL).

¹H-NMR (DMSO-d₆) δ 3.47 (4H, m), 3.81 (2H, t, J=4.5 Hz), 4.61 (2H, t,J=4.5 Hz), 4.70 (1H, t, J=4.5 Hz), 5.27 (2H, s), 6.48 (1H, d, J=3 Hz),7.20 (1H, d, J=9 Hz), 7.37 (1H, dd, J=7 Hz, 4.5 Hz), 7.49 (1H, dd, J=9Hz, 3 Hz), 7.58 (1H, d, J=8 Hz), 7.64 (1H, d, J=3 Hz), 7.84 (1H, d, J=3Hz), 7.88 (1H, m), 8.27 (1H, s), 8.59 (1H, dd, J=3 Hz, 1 Hz), 8.70 (1H,br s).

Example 253

Production ofN-[2-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-2-(methylsulfonyl)acetamide(i) Production of tert-butyl[2-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate

The title compound (812 mg) was obtained as a white powder by the methodin the same manner as in Example 188 (i) using tert-butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (500 mg),3-chloro-4-(pyridin-2-ylmethoxy)aniline (594 mg) and isopropyl alcohol(5 mL).

¹H-NMR (CDCl₃) δ 1.48 (9H, s), 3.46 (2H, m), 4.43 (2H, m), 5.19 (1H, t,J=5 Hz), 5.29 (2H, s), 6.56 (1H, d, J=3 Hz), 6.98 (1H, d, J=9 Hz), 7.14(1H, d, J=3 Hz), 7.2-7.3 (2H, m), 7.6-7.8 (3H, m), 7.87 (1H, d, J=3 Hz),8.46 (1H, s), 8.51 (1H, br s), 8.59 (1H, m).

(ii) Production of5-(2-aminoethyl)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-aminetrihydrochloride

tert-Butyl[2-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate(790 mg) was dissolved in tetrahydrofuran (24 mL)/2N hydrochloric acid(12 mL), and the mixture was stirred at 60° C. for 16 hrs. The reactionmixture was concentrated under reduced pressure, ethanol (30 mL) wasadded to the residue and the mixture was concentrated again underreduced pressure. Ethyl acetate was added to the residue and the solidwas collected by filtration and dried under reduced pressure to give thetitle compound (826 mg) as a solid powder.

¹H-NMR (DMSO-d₆) δ 3.29 (2H, m), 5.07 (2H, m), 5.49 (2H, s), 6.73 (1H,dd, J=3 Hz, 1 Hz), 7.34 (1H, d, J=9 Hz), 7.52 (1H, dd, J=9 Hz, 3 Hz),7.68 (1H, m), 7.74 (1H, d, J=2 Hz), 7.85 (1H, m), 8.09 (1H, d, J=3 Hz),8.24 (1H, m), 8.47 (3H, br s), 8.69 (1H, s), 8.77 (1H, m), 10.19 (1H, brs).

(iii) Production ofN-[2-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-2-(methylsulfonyl)acetamide

The title compound (182 mg) was obtained as colorless powder crystals bythe reaction in the same manner as in Example 155 (iv) using5-(2-aminoethyl)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-aminetrihydrochloride (261 mg), 2-(methylsulfonyl)acetic acid (107 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (149 mg),1-hydroxybenzotriazole monohydrate (105 mg), triethylamine (0.360 mL)and N,N-dimethylformamide (10 mL).

¹H-NMR (DMSO-d₆) δ 3.10 (3H, s), 3.44 (2H, q, J=6 Hz), 4.06 (2H, s),4.53 (2H, t, J=6 Hz), 5.28 (2H, s), 6.46 (1H, d, J=3 Hz), 7.22 (1H, d,J=9 Hz), 7.37 (1H, dd, J=8 Hz, 6 Hz), 7.57 (3H, m), 7.78 (1H, d, J=2Hz), 7.89 (1H, dt, J=2 Hz, 8 Hz), 8.26 (1H, s), 8.49 (1H, br s), 8.60(1H, d, J=5 Hz), 8.67 (1H, t, J=6 Hz).

Example 254

Production of tert-butyl(2S,4R)-4-hydroxy-2-[({2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}amino)carbonyl]pyrrolidine-1-carboxylate

The title compound (310 mg) was obtained as a colorless powder by thereaction in the same manner as in Example 155 (iv) using5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (300 mg),(4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline (118 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (172 mg),1-hydroxybenzotriazole monohydrate (122 mg), triethylamine (0.418 mL)and N,N-dimethylformamide (11.73 mL).

¹H-NMR (CDCl₃) δ 1.43 (9H, s), 1.9-2.1 (2H, m), 2.22 (3H, s), 2.50 (1H,br s), 3.44 (2H, m), 3.61 (2H, m), 4.44 (4H, m), 6.58 (1H, d, J=3 Hz),6.94 (1H, d, J=9 Hz), 7.10 (1H, m), 7.18 (2H, m), 7.27 (2H, m), 7.39(1H, d, J=8 Hz), 7.65 (1H, d, J=9 Hz), 7.73 (1H, m), 8.39 (1H, br s),8.48 (1H, s).

Example 255

Production of(4R)-4-hydroxy-N-{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-L-prolinamidedihydrochloride

tert-Butyl(2S,4R)-4-hydroxy-2-[({2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}amino)carbonyl]pyrrolidine-1-carboxylate(230 mg) was dissolved in dichloromethane (2.39 mL), trifluoroaceticacid (1.79 mL) was added, and the mixture was stirred at roomtemperature for 2 hrs. The reaction mixture was concentrated underreduced pressure, and the residue was dissolved in ethylacetate/tetrahydrofuran (1:1, 50 mL). The organic layer was washed withsaturated aqueous sodium hydrogen carbonate (30 mL), dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas subjected to basic silica gel chromatography (ethylacetate/methanol=100/0→80/20). The fractions containing the titlecompound were collected and concentrated under reduced pressure. Theresidue was dissolved in ethyl acetate, 4N hydrochloric acid (0.252 mL)was added, and the mixture was crystallized to give the title compound(136 mg).

¹H-NMR (DMSO-d₆) δ 1.66 (1H, m), 2.14 (1H, m), 2.21 (3H, s), 3.04 (1H,m), 3.23 (1H, m), 3.49 (3H, m), 3.67 (1H, m), 4.16 (2H, m), 4.36 (1H,m), 4.83 (2H, m), 5.55 (1H, br s), 6.66 (1H, d, J=3 Hz), 7.13 (1H, d,J=9 Hz), 7.23 (2H, m), 7.49 (2H, m), 7.61 (2H, m), 7.94 (1H, m), 8.56(1H, m), 8.68 (1H, s), 8.95 (1H, m), 10.02 (2H, m).

Example 256

Production of2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}acetamidemethanesulfonate

2-(Methylsulfonyl)-N-{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}acetamide(680 mg) was dissolved in ethyl acetate (3.4 mL), methanesulfonic acid(0.0887 mL) was added at 50° C., and the mixture was stirred for 10 min.and further stirred at room temperature for 2 hrs. The precipitatedcrystals were collected by filtration and washed with diisopropyl etherto give the title compound (797 mg) as colorless crystals.

¹H-NMR (DMSO-d₆) δ 2.20 (3H, s), 2.31 (3H, s), 3.05 (3H, s), 3.55 (2H,q, J=6 Hz), 4.06 (2H, s), 4.68 (2H, t, J=6 Hz), 6.65 (1H, d, J=3 Hz),7.13 (1H, d, J=9 Hz), 7.23 (2H, m), 7.49 (2H, m), 7.62 (2H, m), 7.91(1H, d, J=3 Hz), 8.70 (2H, m), 9.84 (1H, br s).

Example 257

Production of2-{2-[4-({3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol

The title compound (133 mg) was obtained as colorless crystals by themethod in the same manner as in Example 183 using2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate(150 mg), 3-chloro-4-[(6-methylpyridin-3-yl)oxy]aniline (152 mg) and1-methyl-2-pyrrolidone (0.863 mL).

¹H-NMR (DMSO-d₆) δ 2.44 (3H, s), 3.48 (4H, m), 3.83 (2H, t, J=4.5 Hz),4.64 (2H, t, J=4.5 Hz), 4.71 (1H, t, J=4.5 Hz), 6.52 (1H, d, J=3 Hz),7.18 (1H, d, J=9 Hz), 7.24 (2H, m), 7.62 (1H, dd, J=9 Hz, 2 Hz), 7.69(1H, d, J=3 Hz), 8.00 (1H, d, J=2 Hz), 8.20 (1H, d, J=1 Hz), 8.34 (1H,s), 8.96 (1H, br s).

Example 258

Production ofN-{2-[4-({3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide(i) Production of tert-butyl{2-[4-({3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate

The title compound (673 mg) was obtained as a white powder by the methodin the same manner as in Example 188 (i) using tert-butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (500 mg),3-chloro-4-[(6-methylpyridin-3-yl)oxy]aniline (594 mg) and isopropylalcohol (5 mL).

¹H-NMR (CDCl₃) δ 1.49 (9H, s), 2.53 (3H, s), 3.48 (2H, m), 4.46 (2H, m),5.26 (1H, t, J=6 Hz), 6.59 (1H, d, J=3 Hz), 7.01 (1H, d, J=9 Hz), 7.09(1H, d, J=8 Hz), 7.18 (2H, m), 7.85 (1H, dd, J=9 Hz, 3 Hz), 8.00 (1H, d,J=3 Hz), 8.30 (1H, d, J=3 Hz), 8.50 (1H, s), 8.63 (1H, br s).

(ii) Production of5-(2-aminoethyl)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminetrihydrochloride

tert-Butyl{2-[4-({3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate(643 mg) was dissolved in tetrahydrofuran (19.5 mL)/2N hydrochloric acid(9.75 mL), and the mixture was stirred at 60° C. for 16 hrs. Thereaction mixture was concentrated under reduced pressure, ethanol (50mL) was added to the residue and the mixture was concentrated againunder reduced pressure. Ethyl acetate was added to the residue and thesolid was collected by filtration and dried under reduced pressure togive the title compound (646 mg) as a solid powder.

¹H-NMR (DMSO-d₆) δ 2.68 (3H, d, J=6 Hz), 3.30 (2H, m), 5.14 (2H, m),6.77 (1H, d, J=3 Hz), 7.40 (1H, m), 7.6-7.9 (2H, m), 8.00 (2H, m), 8.12(1H, m), 8.52 (4H, m), 8.77 (1H, s), 10.50 (1H, m).

(iii) Production ofN-{2-[4-({3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide

The title compound (230 mg) was obtained as colorless powder crystals bythe reaction in the same manner as in Example 155 (iv) using5-(2-aminoethyl)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminetrihydrochloride (261 mg), 2-(methylsulfonyl)acetic acid (107 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (149 mg),1-hydroxybenzotriazole monohydrate (105 mg), triethylamine (0.360 mL)and N,N-dimethylformamide (10 mL).

¹H-NMR (DMSO-d₆) δ 2.45 (3H, s), 3.10 (3H, s), 3.45 (2H, q, J=6 Hz),4.04 (2H, s), 4.56 (2H, t, J=6 Hz), 6.50 (1H, d, J=3 Hz), 7.18 (1H, d,J=9 Hz), 7.25 (1H, d, J=2 Hz), 7.62 (1H, d, J=3 Hz), 7.70 (1H, dd, J=9Hz, 3 Hz), 7.95 (1H, d, J=2 Hz), 8.22 (1H, m), 8.34 (1H, s), 8.67 (2H,m).

Example 259

Production of2-{2-[4-({3-chloro-4-[(5-chloropyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol

The title compound (145 mg) was obtained as colorless crystals by themethod in the same manner as in Example 183 using2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate(150 mg), 3-chloro-4-[(5-chloropyridin-3-yl)oxy]aniline (165 mg) and1-methyl-2-pyrrolidone (0.863 mL).

¹H-NMR (DMSO-d₆) δ 3.49 (4H, m), 3.84 (2H, t, J=4.5 Hz), 4.65 (2H, t,J=4.5 Hz), 4.72 (1H, t, J=4.5 Hz), 6.53 (1H, d, J=3 Hz), 7.33 (1H, d,J=9 Hz), 7.49 (1H, m), 7.69 (2H, m), 8.04 (1H, d, J=2 Hz), 8.32 (1H, d,J=2 Hz), 8.36 (1H, s), 8.40 (1H, d, J=2 Hz), 9.02 (1H, br s).

Example 260

Production ofN-{2-[4-({3-chloro-4-[(5-chloropyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide(i) Production of tert-butyl{2-[4-({3-chloro-4-[(5-chloropyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate

The title compound (769 mg) was obtained as a white powder by the methodin the same manner as in Example 188 (i) using tert-butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (500 mg),3-chloro-4-[(5-chloropyridin-3-yl)oxy]aniline (643 mg) and isopropylalcohol (5 mL).

¹H-NMR (CDCl₃) δ 1.50 (9H, s), 3.49 (2H, m), 4.48 (2H, m), 5.21 (1H, t,J=6 Hz), 6.60 (1H, d, J=3 Hz), 7.11 (1H, d, J=9 Hz) 7.21 (2H, m), 7.94(1H, dd, J=9 Hz, 3 Hz), 8.06 (1H, d, J=3 Hz), 8.29 (2H, m), 8.53 (1H,s), 8.69 (1H, br s).

(ii) Production of5-(2-aminoethyl)-N-{3-chloro-4-[(5-chloropyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminetrihydrochloride

tert-Butyl{2-[4-({3-chloro-4-[(5-chloropyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate(700 mg) was dissolved in tetrahydrofuran (19.5 mL)/2N hydrochloric acid(9.75 mL), and the mixture was stirred at 60° C. for 16 hrs. Thereaction mixture was concentrated under reduced pressure, ethanol (50mL) was added to the residue and the mixture was concentrated againunder reduced pressure. Ethyl acetate was added to the residue and thesolid was collected by filtration and dried under reduced pressure togive the title compound (663 mg) as a solid powder.

¹H-NMR (DMSO-d₆) δ 3.30 (2H, m), 5.09 (2H, m), 6.77 (1H, d, J=3 Hz),7.40 (1H, d, J=9 Hz), 7.61 (1H, m), 7.69 (1H, dd, J=9 Hz, 2 Hz), 7.96(1H, d, J=2 Hz), 8.12 (1H, d, J=3 Hz), 8.35 (1H, d, J=2 Hz), 8.40 (3H,s), 8.46 (1H, d, J=2 Hz), 8.77 (1H, s), 10.36 (1H, m).

(iii) Production ofN-{2-[4-({3-chloro-4-[(5-chloropyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide

The title compound (255 mg) was obtained as colorless powder crystals bythe reaction in the same manner as in Example 155 (iv) using5-(2-aminoethyl)-N-{3-chloro-4-[(5-chloropyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminetrihydrochloride (271 mg), 2-(methylsulfonyl)acetic acid (107 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (149 mg),1-hydroxybenzotriazole monohydrate (105 mg), triethylamine (0.360 mL)and N,N-dimethylformamide (10 mL).

¹H-NMR (DMSO-d₆) δ 3.09 (3H, s), 3.45 (2H, m), 4.04 (2H, s), 4.56 (2H,t, J=6 Hz), 6.50 (1H, d, J=3 Hz), 7.34 (1H, d, J=9 Hz), 7.50 (1H, m),7.63 (1H, d, J=3 Hz), 7.76 (1H, dd, J=9 Hz, 2 Hz), 7.99 (1H, d, J=3 Hz),8.32 (1H, d, J=2 Hz), 8.35 (1H, s), 8.40 (1H, d, J=2 Hz), 8.66 (1H, m),8.73 (1H, br s).

Example 261

Production of tert-butyl4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy]piperidine-1-carboxylate(i) Production of tert-butyl4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino]-2-chlorophenoxy}piperidine-1-carboxylate

A mixture of 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethylbenzoate (3.46 g), tert-butyl4-(4-amino-2-chlorophenoxy)piperidine-1-carboxylate (3.27 g) andisopropyl alcohol (50 mL) was stirred at 80° C. overnight. The reactionmixture was concentrated under reduced pressure, water and saturatedaqueous sodium hydrogen carbonate solution were added, and the mixturewas extracted with ethyl acetate. The ethyl acetate layer was washedwith saturated brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the obtained residuewas subjected to silica gel column chromatography (eluent,methanol:ethyl acetate=0:100→10:90). The object fraction wasconcentrated under reduced pressure. The residue was crystallized fromethyl acetate-diisopropyl ether to give the title compound (4.70 g) as awhite powder.

¹H-NMR (CDCl₃) δ 1.48 (9H, s), 1.71-1.92 (4H, m), 3.33-3.45 (2H, m),3.62-3.73 (2H, m), 3.90-3.97 (2H, m), 4.05 (2H, t, J=4.4 Hz), 4.29-4.39(1H, m), 4.46-4.52 (2H, m), 4.56 (2H, t, J=4.4 Hz), 6.61 (1H, d, J=3.3Hz), 6.72 (1H, d, J=8.7 Hz), 7.19 (1H, d, J=3.3 Hz), 7.29 (1H, dd,J=8.7, 2.7 Hz), 7.33-7.40 (2H, m), 7.50-7.57 (1H, m), 7.69 (1H, d, J=2.7Hz), 7.78-7.83 (2H, m), 8.47 (1H, s), 8.55 (1H, br s).

(ii) Production of tert-butyl4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy]piperidine-1-carboxylate

tert-Butyl4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino]-2-chlorophenoxy}piperidine-1-carboxylate(636 mg) was dissolved in a mixed solvent of methanol (10 mL) andtetrahydrofuran (10 mL), 1N aqueous sodium hydroxide solution (2 mL) wasadded, and the mixture was stirred overnight at room temperature. Waterwas added to the reaction mixture and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brineand dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure and the obtained residue was subjected to basicsilica gel column chromatography (eluent, methanol:ethylacetate=0:100→10:90). The object fraction was concentrated under reducedpressure. The solvent was evaporated under reduced pressure and theobtained residue was crystallized from ethyl acetate-diethyl ether togive the title compound (498 mg) as a white powder.

¹H-NMR (CDCl₃) δ 1.47 (9H, s), 1.75-1.96 (4H, m), 2.27 (1H, br s),3.33-3.45 (2H, m), 3.63-3.82 (6H, m), 4.00 (2H, t, J=4.5 Hz), 4.39-4.47(1H, m), 4.54 (2H, t, J=4.5 Hz), 6.58 (1H, d, J=3.3 Hz), 6.95 (1H, d,J=8.8 Hz), 7.17 (1H, d, J=3.3 Hz), 7.52 (1H, dd, J=8.8, 2.7 Hz), 7.70(1H, d, J=2.7 Hz), 8.46 (1H, s), 8.60 (1H, br s).

Example 262

Production of4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy]-N-(2,6-difluorophenyl)piperidine-1-carboxamidehydrochloride (i) Production of2-[2-(4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethylbenzoate dihydrochloride

4N Hydrochloric acid/ethyl acetate solution (20 mL) and ethanol (10 mL)were added to tert-butyl4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino]-2-chlorophenoxy}piperidine-1-carboxylate(3.82 g), and the mixture was stirred at room temperature for 5 hrs. Thereaction mixture was concentrated under reduced pressure, and theobtained residue was crystallized from ethanol-ethyl acetate to give thetitle compound (3.68 g) as a white powder.

¹H-NMR (DMSO-d₆) δ 1.85-2.00 (2H, m), 2.07-2.21 (2H, m), 3.02-3.28 (4H,m), 3.77 (2H, m), 3.88 (2H, m), 4.29 (2H, m), 4.70-4.79 (1H, m), 4.89(2H, m), 6.60 (1H, d, J=3.0 Hz), 7.25 (1H, d, J=8.7 Hz), 7.42-7.51 (3H,m), 7.61-7.73 (4H, m), 7.98 (1H, d, J=3.0 Hz), 8.57 (1H, s), 9.20-9.50(2H, m), 9.85 (1H, br s).

(ii) Production of4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy]-N-(2,6-difluorophenyl)piperidine-1-carboxamidehydrochloride

To a mixture of2-[2-(4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethylbenzoate dihydrochloride (305 mg), 10% aqueous sodium carbonate solution(10 mL), ethyl acetate (15 mL) and tetrahydrofuran (5 mL) was added2,6-difluorophenyl isocyanate (93 mg) with vigorous stirring. Themixture was stirred at room temperature for 2 hrs, water was added andthe mixture was extracted with ethyl acetate. The ethyl acetate layerwas washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theobtained residue was dissolved in methanol (8 mL) and tetrahydrofuran (2mL). 1N Aqueous sodium hydroxide solution (1 mL) was added, and themixture was stirred at room temperature for 3 hrs. Water was added tothe reaction mixture and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the obtained residue was subjected to basic silica gelcolumn chromatography (eluent, methanol:ethyl acetate=0:100→15:85). Theobject fraction was concentrated under reduced pressure. The residue wasdissolved in ethyl acetate-ethanol, and 1N hydrochloric acid/ethylacetate solution (0.5 mL) was added. The solvent was evaporated underreduced pressure and the obtained residue was crystallized fromethanol-ethyl acetate to give the title compound (202 mg) as a whitepowder.

¹H-NMR (DMSO-d₆) δ 1.60-1.75 (2H, m), 1.91-2.04 (2H, m), 3.20-3.55 (6H,m), 3.68-3.81 (2H, m), 3.84 (2H, m), 4.72-4.85 (3H, m), 6.67 (1H, d,J=3.0 Hz), 7.06-7.17 (2H, m), 7.23-7.32 (1H, m), 7.35 (1H, d, J=8.9 Hz),7.51 (1H, dd, J=8.9, 2.5 Hz), 7.77 (1H, d, J=2.5 Hz), 7.99 (1H, d, J=3.0Hz), 8.34 (1H, s), 8.68 (1H, s), 9.79 (1H, br s).

Example 263

Production of2-(2-{4-[(3-chloro-4-{[1-(cyclopentylcarbonyl)piperidin-4-yl]oxy}phenyl)amino]-5H-pyrrolo[3,2-d]pyrimidin-5-yl}ethoxy)ethanolhydrochloride

The title compound (207 mg) was obtained as a white powder by the methodin the same manner as in Example 262 (ii) using2-[2-(4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethylbenzoate dihydrochloride (305 mg), 10% aqueous sodium carbonate solution(10 mL), ethyl acetate (15 mL), tetrahydrofuran (5 mL) andcyclopentanecarbonyl chloride (80 mg).

¹H-NMR (DMSO-d₆) δ 1.45-2.06 (12H, m), 2.95-3.08 (1H, m), 3.30-3.55 (6H,m), 3.69-3.80 (2H, m), 3.83 (2H, t, J=4.4 Hz), 4.70-4.85 (3H, m), 6.67(1H, d, J=3.0 Hz), 7.34 (1H, d, J=9.0 Hz), 7.50 (1H, dd, J=9.0, 2.7 Hz),7.76 (1H, d, J=2.7 Hz), 7.99 (1H, d, J=3.0 Hz), 8.68 (1H, s), 9.82 (1H,br s).

Example 264

Production of4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy]-N-cyclopentylpiperidine-1-carboxamidehydrochloride

To a solution of 1,1′-carbonylbis(1H-imidazole) (162 mg) intetrahydrofuran (5 mL) was added a solution of cyclopentylamine (85 mg)in tetrahydrofuran (1 mL), and the mixture was stirred at roomtemperature for 1 hr. A solution of2-[2-(4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethylbenzoate dihydrochloride (305 mg) and triethylamine (0.153 mL) intetrahydrofuran (1 mL) was added, and the mixture was stirred overnightat room temperature. Water was added to the reaction mixture and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the obtainedresidue was dissolved in methanol (8 mL) and tetrahydrofuran (2 mL). 1NAqueous sodium hydroxide solution (1 mL) was added, and the mixture wasstirred overnight at room temperature. Water was added to the reactionmixture and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe obtained residue was subjected to basic silica gel columnchromatography (eluent, methanol:ethyl acetate=0:100→10:90). The objectfraction was concentrated under reduced pressure. The residue wasdissolved in ethyl acetate-ethanol, and 1N hydrochloric acid/ethylacetate solution (0.5 mL) was added. The solvent was evaporated underreduced pressure and the obtained residue was crystallized fromethanol-ethyl acetate to give the title compound (188 mg) as a whitepowder.

¹H-NMR (DMSO-d₆) δ 1.30-1.95 (12H, m), 3.15-3.27 (2H, m), 3.40-3.50 (4H,m), 3.55-3.67 (2H, m), 3.83 (2H, t, J=4.6 Hz), 3.82-3.98 (1H, m),4.62-4.72 (1H, m), 4.80 (2H, m), 6.30 (1H, d, J=6.4 Hz), 6.67 (1H, d,J=3.0 Hz), 7.32 (1H, d, J=9.0 Hz), 7.50 (1H, dd, J=9.0, 2.6 Hz), 7.75(1H, d, J=2.6 Hz), 7.99 (1H, d, J=3.0 Hz), 8.68 (1H, s), 9.82 (1H, brs).

Example 265

Production of4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy]-N-(4-methoxyphenyl)piperidine-1-carboxamidehydrochloride

The title compound (209 mg) was obtained as a white powder by the methodin the same manner as in Example 262 (ii) using2-[2-(4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethylbenzoate dihydrochloride (305 mg), 10% aqueous sodium carbonate solution(10 mL), ethyl acetate (15 mL), tetrahydrofuran (5 mL) and4-methoxyphenyl isocyanate (75 mg).

¹H-NMR (DMSO-d₆) δ 1.60-1.75 (2H, m), 1.90-2.03 (2H, m), 3.34-3.51 (6H,m), 3.68-3.80 (2H, m), 3.70 (3H, s), 3.84 (2H, t, J=4.5 Hz), 4.70-4.85(3H, m), 6.68 (1H, d, J=3.2 Hz), 6.82 (2H, d, J=9.1 Hz), 7.31-7.40 (3H,m), 7.51 (1H, dd, J=8.9, 2.6 Hz), 7.77 (1H, d, J=2.6 Hz), 7.99 (1H, d,J=3.2 Hz), 8.44 (1H, br s), 8.68 (1H, s), 9.81 (1H, br s).

Example 266

Production of4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy]-N-(4-methylphenyl)piperidine-1-carboxamidehydrochloride

The title compound (190 mg) was obtained as a white powder by the methodin the same manner as in Example 262 (ii) using2-[2-(4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethylbenzoate dihydrochloride (305 mg), 10% aqueous sodium carbonate solution(10 mL), ethyl acetate (15 mL), tetrahydrofuran (5 mL) and4-methylphenyl isocyanate (67 mg).

¹H-NMR (DMSO-d₆) δ 1.60-1.75 (2H, m), 1.90-2.03 (2H, m), 2.23 (3H, s),3.34-3.51 (6H, m), 3.69-3.80 (2H, m), 3.84 (2H, t, J=4.5 Hz), 4.69-4.84(3H, m), 6.67 (1H, d, J=3.0 Hz), 7.03 (2H, d, J=8.5 Hz), 7.31-7.39 (3H,m), 7.51 (1H, dd, J=8.9, 2.7 Hz), 7.76 (1H, d, J=2.7 Hz), 7.99 (1H, d,J=3.0 Hz), 8.50 (1H, br s), 8.68 (1H, s), 9.82 (1H, br s).

Example 267

Production of tert-butyl4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy]benzoatehydrochloride (i) Production of tert-butyl4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino]-2-chlorophenoxy}benzoate

A mixture of 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethylbenzoate (1.46 g), tert-butyl 4-(4-amino-2-chlorophenoxy)benzoate (1.35g) and isopropyl alcohol (30 mL) was stirred at 80° C. overnight. Thereaction mixture was concentrated under reduced pressure, water andsaturated aqueous sodium hydrogen carbonate solution were added, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the obtainedresidue was subjected to silica gel column chromatography (eluent, ethylacetate). The object fraction was concentrated under reduced pressureand the residue was crystallized from ethyl acetate-diethyl ether togive the title compound (1.54 g) as a white powder.

¹H-NMR (CDCl₃) δ 1.59 (9H, s), 3.93-3.99 (2H, m), 4.05-4.11 (2H, m),4.46-4.52 (2H, m), 4.55-4.61 (2H, m), 6.64 (1H, d, J=3.2 Hz), 6.82-6.90(3H, m), 7.22 (1H, d, J=3.2 Hz), 7.30-7.40 (3H, m), 7.47-7.54 (1H, m),7.76-7.81 (2H, m), 7.90 (1H, d, J=2.6 Hz), 7.94 (2H, d, J=9.1 Hz), 8.51(1H, s), 8.78 (1H, br s).

(ii) Production of tert-butyl4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy]benzoatehydrochloride

tert-Butyl4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino]-2-chlorophenoxy}benzoate(189 mg) was dissolved in a mixed solvent of methanol (5 mL) andtetrahydrofuran (1 mL), 1N aqueous sodium hydroxide solution (0.6 mL)was added, and the mixture was stirred overnight at room temperature.Water was added to the reaction mixture and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the obtained residue was subjectedto basic silica gel column chromatography (eluent, methanol:ethylacetate=0:100→10:90). The object fraction was concentrated under reducedpressure. The residue was dissolved in ethyl acetate-ethanol, and 1Nhydrochloric acid/ethyl acetate solution (0.3 mL) was added. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from ethanol-ethyl acetate to give the title compound (163mg) as a white powder.

¹H-NMR (DMSO-d₆) δ 1.54 (9H, s), 3.41-3.52 (4H, m), 3.85 (2H, m), 4.84(2H, m), 6.71 (1H, d, J=3.2 Hz), 7.02 (2H, d, J=8.9 Hz), 7.36 (1H, d,J=8.9 Hz), 7.69 (1H, dd, J=8.9, 2.4 Hz), 7.93 (2H, d, J=8.9 Hz), 8.00(1H, d, J=2.4 Hz), 8.04 (1H, d, J=3.2 Hz), 8.75 (1H, s), 10.00 (1H, brs).

Example 268

Production ofN-(tert-butyl)-4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy]benzamidehydrochloride (i) Production of4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino]-2-chlorophenoxy}benzoicacid hydrochloride

Trifluoroacetic acid (10 mL) was added to tert-butyl4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino]-2-chlorophenoxy}benzoate(1.26 g), and the mixture was stirred at room temperature for 3 hrs. Thereaction mixture was concentrated under reduced pressure, 4Nhydrochloric acid/ethyl acetate solution was added, and the mixture wasconcentrated again under reduced pressure. The obtained residue wascrystallized from ethyl acetate to give the title compound (1.16 g) as awhite powder.

¹H-NMR (DMSO-d₆) δ 3.76-3.83 (2H, m), 3.92 (2H, t, J=4.4 Hz), 4.26-4.34(2H, m), 4.89 (2H, m), 6.63 (1H, d, J=3.4 Hz), 6.98 (2H, d, J=8.8 Hz),7.27 (1H, d, J=8.8 Hz), 7.41-7.50 (2H, m), 7.55-7.73 (4H, m), 7.92-8.03(4H, m), 8.66 (1H, s), 9.91 (1H, br).

(ii) Production ofN-(tert-butyl)-4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy]benzamidehydrochloride

A mixture of4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino]-2-chlorophenoxy}benzoicacid hydrochloride (183 mg), 2-methylpropan-2-amine (0.038 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg),1-hydroxybenzotriazole monohydrate (55 mg), triethylamine (0.050 mL) andN,N-dimethylformamide (3 mL) was stirred overnight at room temperature.Water was added to the reaction mixture and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the obtained residue was subjectedto silica gel column chromatography (eluent, methanol:ethylacetate=0:100→10:90). The object fraction was concentrated under reducedpressure. The residue was dissolved in a mixed solvent of methanol (5mL) and tetrahydrofuran (1 mL), 1N aqueous sodium hydroxide solution(0.6 mL) was added and the mixture was stirred at room temperature for 3days. Water was added to the reaction mixture and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the obtained residue wassubjected to basic silica gel column chromatography (eluent,methanol:ethyl acetate=0:100→10:90). The object fraction wasconcentrated under reduced pressure. The residue was dissolved in ethylacetate-ethanol, and 1N hydrochloric acid/ethyl acetate solution (0.3mL) was added. The solvent was evaporated under reduced pressure and theobtained residue was crystallized from ethanol-ethyl acetate to give thetitle compound (118 mg) as a white powder.

¹H-NMR (DMSO-d₆) δ 1.37 (9H, s), 3.41-3.52 (4H, m), 3.85 (2H, m), 4.84(2H, m), 6.71 (1H, d, J=3.2 Hz), 6.97 (2H, d, J=8.8 Hz), 7.29 (1H, d,J=8.8 Hz), 7.67 (1H, dd, J=8.8, 2.5 Hz), 7.72 (1H, s), 7.85 (2H, d,J=8.8 Hz), 7.99 (1H, d, J=2.5 Hz), 8.04 (1H, d, J=3.2 Hz), 8.75 (1H, s),10.00 (1H, br s).

Example 269

Production of4-[2-chloro-4-((5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)phenoxy]-N-(2,2-dimethylpropyl)benzamide

The title compound (140 mg) was obtained as a white powder by the methodin the same manner as in Example 268 (ii) using4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino]-2-chlorophenoxy}benzoicacid hydrochloride (183 mg), neopentylamine (0.042 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg),1-hydroxybenzotriazole monohydrate (55 mg), triethylamine (0.050 mL),N,N-dimethylformamide (3 mL), methanol (5 mL), tetrahydrofuran (1 mL)and 1N aqueous sodium hydroxide solution (0.6 mL).

¹H-NMR (DMSO-d₆) δ 0.90 (9H, s), 3.10 (2H, d, J=6.4 Hz), 3.42-3.52 (4H,m), 3.86 (2H, t, J=4.6 Hz), 4.83 (2H, t, J=4.6 Hz), 6.71 (1H, d, J=2.9Hz), 7.01 (2H, d, J=8.5 Hz), 7.32 (1H, d, J=8.8 Hz), 7.66 (1H, dd,J=8.8, 2.2 Hz), 7.91 (2H, d, J=8.5 Hz), 7.99 (1H, d, J=2.2 Hz), 8.03(1H, d, J=2.9 Hz), 8.32 (1H, t, J=6.4 Hz), 8.75 (1H, s), 9.95 (1H, brs).

Example 270

Production of4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy]-N-(2,2,2-trifluoroethyl)piperidine-1-carboxamidehydrochloride

The title compound (101 mg) was obtained as a white powder by the methodin the same manner as in Example 264 using1,1′-carbonylbis(1H-imidazole) (97 mg), 2,2,2-trifluoroethylamine (0.048mL),2-[2-(4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethylbenzoate dihydrochloride (244 mg), triethylamine (0.123 mL) and 1Naqueous sodium hydroxide solution (0.6 mL).

¹H-NMR (DMSO-d₆) δ 1.53-1.68 (2H, m), 1.84-1.98 (2H, m), 3.25-3.70 (8H,m), 3.77-3.92 (4H, m), 4.66-4.77 (1H, m), 4.79 (2H, t, J=4.8 Hz), 6.67(1H, d, J=3.1 Hz), 7.23 (1H, t, J=6.2 Hz), 7.33 (1H, d, J=9.0 Hz), 7.50(1H, dd, J=9.0, 2.6 Hz), 7.76 (1H, d, J=2.6 Hz), 7.99 (1H, d, J=3.1 Hz),8.68 (1H, s), 9.78 (1H, br s).

Example 271

Production of 2,2,2-trifluoroethyl4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy]piperidine-1-carboxylatehydrochloride

The title compound (135 mg) was obtained as a white powder by the methodin the same manner as in Example 264 using1,1′-carbonylbis(1H-imidazole) (97 mg), 2,2,2-trifluoroethanol (0.044mL),2-[2-(4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethylbenzoate dihydrochloride (244 mg), triethylamine (0.123 mL) and 1Naqueous sodium hydroxide solution (0.6 mL).

¹H-NMR (DMSO-d₆) δ 1.62-1.77 (2H, m), 1.89-2.02 (2H, m), 3.38-3.52 (6H,m), 3.58-3.73 (2H, m), 3.83 (2H, t, J=4.7 Hz), 4.67-4.85 (5H, m), 6.68(1H, d, J=2.9 Hz), 7.34 (1H, d, J=9.0 Hz), 7.51 (1H, dd, J=9.0, 2.5 Hz),7.76 (1H, d, J=2.5 Hz), 7.99 (1H, d, J=2.9 Hz), 8.68 (1H, s), 9.82 (1H,br s).

Example 272

Production ofN-(tert-butyl)-4-(2-chloro-4-{[5-(2-{[(methylsulfonyl)acetyl]amino}ethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl]amino}phenoxy)piperidine-1-carboxamide

tert-Butyl4-(2-chloro-4-{[5-(2-{[(methylsulfonyl)acetyl]amino}ethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl]amino}phenoxy)piperidine-1-carboxylate(120.0 mg) was dissolved in methanol (4.0 mL), 4N hydrochloricacid/ethyl acetate (5 mL) was added, and the mixture was stirred for 5hrs. 8N Aqueous sodium hydroxide solution (5 mL) and water (10 mL) wereadded, and the mixture was extracted with dichloromethane. The extractwas dried over magnesium sulfate and concentrated. The residue was addedto the reaction system, wherein 1,1′-carbonylbis(1H-imidazole) (48.5 mg)and 2-methylpropan-2-amine (22.0 mg) were dissolved in tetrahydrofuran(5.0 mL), and the mixture was stirred for 1 hr. Triethylamine (1.0 mL)was further added dropwise and the mixture was stirred for 1 hr. Underice-cooling, saturated aqueous sodium hydrogen carbonate was added, andthe mixture was extracted with dichloromethane. The extract was driedover magnesium sulfate and concentrated, and the residue was separatedand purified by silica gel column chromatography (eluent, ethylacetate:methanol=100:0→ethyl acetate:methanol=80:20). Crystallizationfrom diethyl ether/ethyl acetate gave the title compound (17.9 mg) ascrystals.

¹H-NMR (DMSO-d₆) δ 1.26 (9H, s), 1.50-1.70 (2H, m), 1.81-1.95 (2H, m),3.10 (3H, s), 3.11-3.65 (6H, m), 4.05 (2H, s), 4.45-4.65 (3H, m), 5.82(1H, s), 6.47 (1H, d, J=3 Hz), 7.22 (1H, d, J=9 Hz), 7.55-7.58 (2H, m),7.75 (1H, d, J=3 Hz), 8.27 (1H, s), 8.48 (1H, s), 8.66 (1H, m).

Example 273

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-N′-methoxyurea

To a solution of N,N′-carbonyldiimidazole (187 mg) inN,N-dimethylformamide (2 mL) were added O-methylhydroxylaminehydrochloride (96 mg) and triethylamine (0.27 mL) under ice-cooling, andthe mixture was stirred at room temperature for 30 min. A solution of5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (200 mg) in N,N-dimethylformamide (5 mL) was added. Thereaction mixture was stirred at room temperature for 22 hrs, aqueoussodium hydrogen carbonate and brine were added under ice-cooling, andthe mixture was extracted twice with ethyl acetate. The organic layerswere collected, dried over anhydrous magnesium sulfate and concentrated.The residue was purified by silica gel column chromatography (eluent,ethyl acetate:methanol=100:0→80:20) and further recrystallized fromethyl acetate/diisopropyl ether to give the title compound (116 mg) ascrystals.

¹H-NMR (CDCl₃) δ: 3.6-3.7 (2H, m), 3.70 (3H, s), 4.5-4.6 (2H, m), 6.14(1H, br s), 6.63 (1H, d, J=3.0 Hz), 7.05 (1H, d, J=9.0 Hz), 7.1-7.5 (5H,m), 7.65-7.75 (1H, m), 8.02 (1H, d, J=2.7 Hz), 8.46 (1H, s), 8.52 (1H,s).

Example 274

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-N′-(2-methoxyethyl)urea

The title compound (147 mg) was obtained as a powder by the reaction inthe same manner as in Example 273 using5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (200 mg), 2-methoxyethylamine (87 mg) andN,N-dimethylformamide (3 mL).

¹H-NMR (DMSO-d₆) δ: 3.05-3.15 (2H, m), 3.12 (3H, s), 3.2-3.5 (4H, m),4.55-4.65 (2H, m), 6.42 (1H, br s), 6.56 (1H, br s), 6.68 (1H, d, J=1.8Hz), 7.25-7.35 (2H, m), 7.36 (1H, d, J=8.7 Hz), 7.52 (1H, d, J=8.1 Hz),7.64 (1H, d, J=9.0 Hz), 7.76 (1H, d, J=9.0 Hz), 7.95-8.05 (2H, m), 8.75(1H, s), 9.12 (1H, s).

Example 275

Production of3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propanenitrile

The title compound (2.02 g) was obtained as a powder by the reaction inthe same manner as in Example 171 using4-chloro-5H-pyrrolo[3,2-d]pyrimidine (3.07 g), N,N-dimethylformamide (30mL), potassium carbonate (4.15 g), 3-bromopropionitrile (3.48 g),3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (2.26 g) and isopropylalcohol (20 mL).

¹H-NMR (DMSO-d₆) δ: 3.01 (2H, t, J=6.4 Hz), 4.83 (2H, t, J=6.4 Hz), 6.58(1H, s), 7.2-7.3 (2H, m), 7.31 (1H, d, J=8.4 Hz), 7.47 (1H, d, J=7.5Hz), 7.55-7.7 (2H, m), 7.7-7.8 (1H, m), 7.87 (1H, s), 8.37 (1H, s), 8.76(1H, s).

Example 276

Production of6-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-8,9-dihydro-3,5,6,9a-tetraazabenzo[cd]azulen-7(6H)-iminedihydrochloride

12N Hydrogen chloride/ethanol (3 mL) was added to3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propanenitrile(200 mg) under ice-cooling, and the mixture was stirred at 0° C. for 2hrs. The reaction mixture was concentrated and the residue was washedwith ethyl acetate and diisopropyl ether to give the title compound (161mg) as a powder.

¹H-NMR (DMSO-d₆) δ: 3.55-3.65 (2H, m), 4.7-4.8 (2H, m), 6.75-6.8 (1H,m), 7.4-7.5 (2H, m), 7.5-7.6 (2H, m), 7.65-7.75 (1H, m), 7.94 (1H, s),8.05-8.1 (1H, m), 8.59 (1H, s), 9.37 (1H, s), 11.29 (1H, s).

Example 277

Production ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-N′-methylguanidinedihydrochloride

To a solution of N-methyl-N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (138 mg) and ethyldiisopropylamine(0.16 mL) in acetonitrile (4 mL) was added5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-aminedihydrochloride (200 mg), and the mixture was stirred at roomtemperature for 4 days. Under ice-cooling, water was added, and themixture was extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by silica gel column chromatography (eluent, ethylacetate:hexane=80:20→100:0). The obtained product was dissolved in ethylacetate, 4N hydrochloric acid/ethyl acetate was added, and the mixturewas stirred at room temperature for 22 hrs. The precipitate wascollected by filtration, and washed with ethyl acetate and diisopropylether to give the title compound (98 mg) as a powder.

¹H-NMR (DMSO-d₆) δ: 2.57 (3H, d, J=3.3 Hz), 3.5-3.7 (2H, m), 4.8-4.9(2H, m), 6.72 (1H, s), 7.25-7.3 (2H, m), 7.38 (1H, d, J=9.0 Hz), 7.4-7.6(3H, m), 7.6-7.75 (3H, m), 8.01 (2H, d, J=8.1 Hz), 8.75 (1H, s), 10.15(1H, s).

Example 278

Production of2-(2-{4-[(3-chloro-4-{4-[3-(1H-imidazol-1-yl)propyl]phenoxy}phenyl)amino]-5H-pyrrolo[3,2-d]pyrimidin-5-yl}ethoxy)ethanoldihydrochloride (i) Production of3-chloro-4-{4-[3-(1H-imidazol-1-yl)propyl]phenoxy}nitrobenzene

To a solution of 4-[3-(1H-imidazol-1-yl)propyl]phenol (405 mg) and3-chloro-4-fluoronitrobenzene (370 mg) in N,N-dimethylformamide (4 mL)was added potassium carbonate (415 mg), and the mixture was stirred atroom temperature for 16 hrs. Under ice-cooling, water was added and themixture was extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by basic silica gel column chromatography (eluent,ethyl acetate:hexane=80:20→100:0) to give the title compound (669 mg) asan oil.

¹H-NMR (CDCl₃) δ: 2.1-2.25 (2H, m), 2.65 (2H, t, J=7.6 Hz), 3.98 (2H, t,J=6.9 Hz), 6.86 (1H, d, J=9.0 Hz), 6.93 (1H, s), 7.02 (1H, d, J=8.6 Hz),7.09 (1H, s), 7.21 (1H, d, J=8.6 Hz), 7.47 (1H, s), 8.04 (1H, dd, J=9.0,2.7 Hz), 8.38 (1H, d, J=2.7 Hz).

(ii) Production of3-chloro-4-{4-[3-(1H-imidazol-1-yl)propyl]phenoxy}aniline

To a solution of3-chloro-4-{4-[3-(1H-imidazol-1-yl)propyl]phenoxy}nitrobenzene (669 mg)in methanol (7 mL) was added 5% Pt/C (140 mg), and the mixture wasstirred under hydrogen atmosphere at room temperature for 16 hrs. 5%Pt/C was filtered off and the filtrate was concentrated. The residue waspurified by basic silica gel column chromatography (eluent, ethylacetate:hexane=80:20→100:0) and further washed with diethyl ether andhexane to give the title compound (277 mg) as a powder.

¹H-NMR (CDCl₃) δ: 2.09 (2H, quintet, J=7.2 Hz), 2.56 (2H, t, J=7.2 Hz),3.67 (2H, br s), 3.93 (2H, t, J=7.2 Hz), 6.56 (1H, dd, J=8.4, 2.7 Hz),6.75-6.95 (5H, m), 7.0-7.1 (3H, m), 7.45 (1H, s).

(iii) Production of2-(2-{4-[(3-chloro-4-{4-[3-(1H-imidazol-1-yl)propyl]phenoxy}phenyl)amino]-5H-pyrrolo[3,2-d]pyrimidin-5-yl}ethoxy)ethanoldihydrochloride

The title compound (99 mg) was obtained as a powder by the reaction inthe same manner as in Example 138 (ii) and (iii) using2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate(207 mg), 3-chloro-4-{4-[3-(1H-imidazol-1-yl)propyl]phenoxy}aniline (197mg) and tetrahydrofuran (4 mL).

¹H-NMR (DMSO-d₆) δ: 2.1-2.3 (2H, m), 2.5-2.7 (2H, m), 3.4-3.6 (2H, m),3.8-3.9 (2H, m), 4.23 (2H, t, J=6.8 Hz), 4.87 (2H, s), 6.71 (1H, d,J=2.4 Hz), 6.92 (2H, d, J=8.1 Hz), 7.14 (1H, d, J=8.1 Hz), 7.25 (2H, d,J=8.4 Hz), 7.6-7.7 (1H, m), 7.70 (1H, s), 7.83 (1H, s), 7.94 (1H, s),8.04 (1H, d, J=3.0 Hz), 8.73 (1H, s), 9.22 (1H, s).

Example 279

Production of2-(2-{4-[(3-chloro-4-{4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenoxy}phenyl)amino]-5H-pyrrolo[3,2-d]pyrimidin-5-yl}ethoxy)ethanol(i) Production of3-chloro-4-{4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenoxy}nitrobenzene

The title compound (721 mg) was obtained as an oil by the reaction inthe same manner as in Example 278 (i) using4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol (435 mg),3-chloro-4-fluoronitrobenzene (370 mg) and N,N-dimethylformamide (4 mL).

¹H-NMR (CDCl₃) δ: 1.6-1.75 (2H, m), 1.9-2.05 (2H, m), 2.68 (2H, t, J=7.4Hz), 4.43 (2H, t, J=7.2 Hz), 6.85 (1H, d, J=9.2 Hz), 7.00 (2H, d, J=8.8Hz), 7.21 (2H, d, J=8.8 Hz), 7.53 (1H, s), 7.72 (1H, s), 8.04 (1H, dd,J=2.6, 9.2 Hz), 8.37 (1H, d, J=2.6 Hz).

(ii) Production of3-chloro-4-{4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenoxy}aniline

The title compound (626 mg) was obtained as an oil by the reaction inthe same manner as in Example 278 (ii) using3-chloro-4-{4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenoxy}nitrobenzene (711mg) and ethyl acetate (10 mL).

¹H-NMR (CDCl₃) δ: 1.55-1.7 (2H, m), 1.8-2.0 (2H, m), 2.60 (2H, t, J=7.5Hz), 3.65 (2H, br s), 4.39 (2H, t, J=7.2 Hz), 6.55 (1H, dd, J=8.7, 2.7Hz), 6.75-6.85 (3H, m), 6.87 (1H, d, J=8.4 Hz), 7.04 (2H, d, J=8.4 Hz),7.49 (1H, d, J=1.0 Hz), 7.69 (1H, d, J=1.0 Hz).

(iii) Production of2-(2-{4-[(3-chloro-4-{4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenoxy}phenyl)amino]-5H-pyrrolo[3,2-d]pyrimidin-5-yl}ethoxy)ethanol

The title compound (293 mg) was obtained as a powder by the reaction inthe same manner as in Example 139 (ii) and (iii) using2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate(346 mg), 3-chloro-4-{4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenoxy}aniline(405 mg) and isopropyl alcohol (5 mL).

¹H-NMR (DMSO-d₆) δ: 1.55-1.7 (2H, m), 1.85-2.0 (2H, m), 2.62 (2H, t,J=7.2 Hz), 3.7-3.75 (2H, m), 3.75-3.8 (2H, m), 4.02 (2H, t, J=4.2 Hz),4.39 (2H, t, J=6.9 Hz), 4.56 (2H, t, J=4.2 Hz), 6.63 (1H, d, J=3.0 Hz),6.88 (2H, d, J=8.7 Hz), 6.98 (1H, d, J=8.4 Hz), 7.08 (2H, d, J=8.7 Hz),7.21 (1H, d, J=3.3 Hz), 7.50 (1H, s), 7.54 (1H, dd, J=8.7, 2.7 Hz), 7.87(1H, d, J=2.7 Hz), 7.69 (1H, s), 8.51 (1H, s), 8.73 (1H, s).

Example 280

Production of2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}acetamidemethanesulfonate

The title compound (1.0 g) was obtained as colorless crystals by thereaction in the same manner as in Example 256 using2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-y]ethyl}acetamide(900 mg), ethyl acetate (4.5 mL) and methanesulfonic acid (0.114 mL).

¹H-NMR (DMSO-d₆) δ 2.19 (3H, s), 2.32 (3H, s), 3.05 (3H, s), 3.55 (2H,q, J=6 Hz), 4.06 (2H, s), 4.68 (2H, t, J=6 Hz), 6.65 (1H, d, J=3 Hz),6.93 (2H, m), 7.12 (2H, m), 7.4-7.6 (3H, m), 7.92 (1H, d, J=3 Hz), 8.70(2H, m), 9.84 (1H, br s).

Formulation Example 1 Amount Per Tablet

(1) Compound obtained in Example 39 10.0 mg (2) Lactose 60.0 mg (3) Cornstarch 35.0 mg (4) Gelatin  3.0 mg (5) Magnesium stearate  2.0 mg

A mixture of 10.0 mg of the compound obtained in Example 39, 60.0 mg oflactose and 35.0 mg of corn starch is granulated through a 1 mm-meshsieve using 0.03 ml of a 10% by weight aqueous solution of gelatin (3.0mg of gelatin), after which the granules are dried at 40° C. andfiltered again. The granules obtained are mixed with 2.0 mg of magnesiumstearate and compressed. The core tablets obtained are coated with asugar coat comprising a suspension of sucrose, titanium dioxide, talcand gum arabic and polished with beeswax to yield sugar-coated tablets.

Formulation Example 2 Dose Per Tablet

(1) Compound obtained in Example 39 10.0 mg (2) Lactose 70.0 mg (3) Cornstarch 50.0 mg (4) Soluble starch  7.0 mg (5) Magnesium stearate  3.0 mg

10.0 mg of the compound obtained in Example 39 and 3.0 mg of magnesiumstearate are granulated using 0.07 ml of an aqueous solution of solublestarch (7.0 mg of soluble starch), after which these granules are driedand mixed with 70.0 mg of lactose and 50.0 mg of corn starch. Thismixture is compressed to yield tablets.

Experimental Example 1A Cloning of human HER2 gene and preparation ofrecombinant baculovirus Human HER2 gene was cloned by RT-PCR using totalRNA prepared from MCF7 cells as a template. The primer used for RT-PCRwas prepared from nucleotide sequence (Genbank Accession M11730)information of HER2 gene by adding a nucleotide sequence encoding flagpeptide and a restriction enzyme recognition sequence to a nucleotidesequence (2176-3918 of Genbank Accession M11730) encoding the HER2intracellular domain region, so that the protein contains an N-terminalFlag tag. The primer nucleotide sequence is shown below.

HER2-U: (SEQ ID NO:1) 5′-AATTAAGTCGACATGGACTACAAAGACGATGACGACAAGCGACGGCAGCAGAAGATCCGGAAGTAC-3′ and HER2-L: (SEQ ID NO:2)5′-AATTAAGCATGCTCACACTGGCACGTCCAGACCCAGGTACTC-3′

The RT reaction was conducted using SuperScript First-Strand SynthesisSystem for RT-PCR (Invitrogen) and the PCR reaction was conducted usinga KOD-plus kit (TOYOBO). The obtained PCR product was electrophoresed onagarose gel (1%), the DNA fragment amplified by PCR was recovered fromthe gel, and then digested with restriction enzymes Sal I and Sph I. TheDNA treated with the restriction enzymes was electrophoresed on agarosegel (1%), and the obtained DNA fragment was recovered and ligated toplasmid pFASTBAC1 (Invitrogen) digested with restriction enzymes Sal Iand Sph I to give expression plasmid pFB-HER2. The nucleotide sequenceof the insertion fragment was confirmed and found to be identical withthe nucleotide sequence (2176-3918 of Genbank Accession M11730) of HER2intracellular domain. Furthermore, using BAC-TO-BAC BaculovirusExpression System (Invitrogen), recombinant baculovirus BAC-HER2 wasprepared.

Experimental Example 1B Preparation of HER2 Intracellular Domain Protein

SF-21 cells were sown at 1×10⁶ cells/mL to Sf-900II SFM medium (1 L,Invitrogen) containing 10% fetal bovine serum (trace), 50 mg/Lgentamicin (Invitrogen) and 0.1% Pluronic F-68 (Invitrogen), and shakingculture was performed using a 2 L volume Erlenmeyer flask at 27° C., 100rpm. After culturing for 24 hrs, recombinant baculovirus BAC-HER2 (13.4mL) was added, and the mixture was further cultured for 3 days. Theculture medium was centrifuged at 2,000 rpm for 5 min. to givevirus-infected cells. The infected cells were washed with a phosphatebuffered saline (Invitrogen), centrifuged under the same conditions, andthe cells were preserved at −80° C. The cryopreserved cells were thawedin ice, suspended in buffer A (50 mM Tris buffer (30 mL, pH 7.4)containing 20% glycerol, 0.15 M NaCl) supplemented with CompleteProtease Inhibitor (Boehringer), and ruptured 3 times with a Polytronhomogenizer (Kinematica) at 20,000 rpm for 30 sec. The rupture mediumwas clarified by centrifugation at 40,000 rpm for 30 min. and filteredwith a 0.45 μm filter. The filtrate was passed through a column packedwith Anti-FLAG M2 Affinity Gel (4 mL, Sigma) at a flow rate of about 0.5mL/min. The column was washed with buffer A, and eluted with buffer Acontaining 100 μg/mL of FLAG peptide. The eluate was concentrated withVivaspin 20 (Vivascience) having a molecular weight cut off of 30K. Theconcentrate was purified by gel filtration using Hi Load Superdex 200 μg16/60 (Amersham Bioscience) equilibrated with buffer A. The fractionscontaining HER2 intracellular domain were collected, glycerol was addedto the final concentration of 50% and cryopreserved at −80° C.

Experimental Example 1C Determination of HER2 Kinase Inhibitory Activity

A test compound dissolved in dimethyl sulfoxide (DMSO) was diluted witha buffer for kinase reaction (50 mM Tris-HCl (pH7.5), 5 mM MgCl₂, 5 mMMnCl₂, 2 mM dithiothreitol, 0.01% Tween-20). To this compound solution(10 μL) was added a buffer for kinase reaction (20 μL) containing 5μg/mL of HER2 intracellular domain obtained in Experimental Example 1Band 12.5 μg/mL of polypeptide substrate poly-Glu:Tyr (4:1) (Sigma). Tothe obtained mixture was added 20 μL of ATP solution (1.25 μM ATP, 0.05μCi [γ-³²P]ATP), the mixture was allowed to react at 25° C. for 10 min.and the reaction was quenched with 50 μL of 20% TCA solution. Thereaction solution was allowed to stand at 4° C. for 20 min., and theacid insoluble fraction was transferred to GF/C filter (PerkinElmer)using cell harvester (PerkinElmer) and washed with 250 mM phosphoricacid solution. After washing, the plate was dried at 45° C. for 60 min.,and 35 μL of MicroScinti 0 (PerkinElmer) was added. The radioactivitywas measured using TopCount (PerkinElmer). HER2 kinase inhibitory rate(%) of the test compound was calculated by the following formula:

Inhibitory rate (%)=(1−(count of testcompound−blank)÷(control−blank))×100

The count of the solution reacted without addition of the compound wasused as a “control”, and the count of the solution without the compoundand HER2 intracellular domain was used as a “blank”. The results of theinhibitory rate of the compounds are shown in Table 1.

From the foregoing, it was shown that the compounds of the presentinvention strongly inhibited the activity of HER2 kinase.

TABLE 1 Example No. (compound No.) Inhibitory rate (%) at 1.0 μM 13 94.938 95.9 39 96.1 158 87.0 190 95.9 191 100

Experimental Example 2A Cloning of human EGF receptor gene andpreparation of recombinant baculovirus Human EGF receptor gene wascloned by RT-PCR using total RNA prepared from A431 cells as a template.The primer for RT-PCR was prepared from nucleotide sequence (GenbankAccession XM_(—)167493) information of EGF receptor gene by adding anucleotide sequence encoding flag peptide and a restriction enzymerecognition sequence to a nucleotide sequence (2182-3810 of GenbankAccession XM_(—)167493) encoding EGF receptor intracellular domainregion, so that the protein contains an N-terminal Flag tag. The primernucleotide sequence is shown below.

EGFR-U: (SEQ ID NO:3) 5′-AATTAAGTCGACATGGACTACAAAGACGATGACGACCGAAGGCGCCACATCGTTCGGAAGCGCACG-3′ and EGFR-L: (SEQ ID NO:4)5′-AATTAAGCATGCTCATGCTCCAATAAATTCACTGCTTTGTGG-3′

The RT reaction was conducted using SuperScript First-Strand SynthesisSystem for RT-PCR (Invitrogen) and the PCR reaction was conducted usinga KOD-plus kit (TOYOBO). The obtained PCR product was electrophoresed onagarose gel (1%), the DNA fragment amplified by PCR was recovered fromthe gel, and then digested with restriction enzymes Sal I and Sph I. TheDNA treated with the restriction enzymes was electrophoresed on agarosegel (1%), and the obtained DNA fragment was recovered and ligated toplasmid pFASTBAC1 (Invitrogen) digested with restriction enzymes Sal Iand Sph I to give expression plasmid pFB-EGFR. The nucleotide sequenceof insertion fragment was confirmed and found to be identical with thenucleotide sequence (2182-3810 of Genbank Accession XM_(—)167493) ofEGFR intracellular domain. Furthermore, using BAC-TO-BAC BaculovirusExpression System (Invitrogen), virus stock BAC-EGFR of recombinantbaculovirus was prepared.

Experimental Example 2B Preparation of EGF Receptor Intracellular DomainProtein

SF-21 cells were sown at 1×10⁶ cells/mL to Sf-900II SFM medium (1 L,Invitrogen) containing 10% fetal bovine serum (trace), 50 mg/Lgentamicin (Invitrogen) and 0.1% Pluronic F-68 (Invitrogen), and shakingculture was performed using a 2 L volume Erlenmeyer flask at 27° C., 100rpm. After culturing for 24 hrs, recombinant baculovirus BAC-EGFR (13.4mL) was added, and the mixture was further cultured for 3 days. Theculture medium was centrifuged at 2,000 rpm for 5 min. to givevirus-infected cells. The infected cells were washed with a phosphatebuffered saline (Invitrogen), centrifuged under the same conditions, andthe cells were preserved at −80° C. The cryopreserved cells were thawedin ice, suspended in buffer A (50 mM Tris buffer (30 mL, pH7.4)containing 20% glycerol, 0.15 M NaCl) supplemented with CompleteProtease Inhibitor (Boehringer), and ruptured 3 times with a Polytronhomogenizer (Kinematica) at 20,000 rpm for 30 sec. The ruptured mediumwas clarified by centrifugation at 40,000 rpm for 30 min. and filteredwith a 0.45 μm filter. The filtrate was passed through a column packedwith Anti-FLAG M2 Affinity Gel (4 mL, Sigma) at a flow rate of about 0.5mL/min. The column was washed with buffer A, and eluted with buffer Acontaining 100 μg/mL of FLAG peptide. The eluate was concentrated withVivaspin 20 (Vivascience) having a molecular weight cut off of 30K. Thebuffer of this concentrate was exchanged using NAPE column (AmershamBioscience) equilibrated with buffer A. The fractions containing EGFreceptor intracellular domain protein were collected, glycerol was addedto the final concentration of 50% and cryopreserved at −80° C.

Experimental Example 2C Determination of EGF Receptor Kinase InhibitoryActivity

A test compound dissolved in dimethyl sulfoxide (DMSO) was diluted witha buffer (50 mM Tris-HCl (pH 7.5), 5 mM MgCl₂, 5 mM MnCl₂, 2 mMdithiothreitol, 0.01% Tween-20). To this compound solution (5 μL) wasadded a buffer (10 μL) containing 250 ng/mL of EGF receptorintracellular domain protein and 250 ng/mL of biotin labeled polypeptidebiotinyl-poly-Glu:Tyr (4:1) (CIS bio International). To the obtainedmixture was added a buffer (10 μL) containing ATP (5 μM), the mixturewas allowed to react at 25° C. for 10 min. and the reaction was quenchedwith 25 μL of a stop solution (100 mM EDTA disodium salt, 62.5 mM HEPESbuffer (pH 7.4), 250 mM NaCl, 0.1% bovine serum albumin, 10 μg/mLAlphaScreen assay streptavidin donor beads (Streptavidin Donor beads:PerkinElmer), 10 μg/mL AlphaScreen assay anti-phosphotyrosinerecognition antibody PY-100 binding acceptor beads (Anti-phosphotyrosine(P-Tyr-100) Acceptor beads: PerkinElmer)). The reaction solution wasallowed to stand at 25° C. for 16 hrs, and the cells were counted usinga plate reader Fusions (PerkinElmer). The kinase inhibitory rate (%) ofthe test compound was calculated by the following formula:

Inhibitory rate (%)=(1−(count of testcompound−blank)÷(control−blank))×100

The count of the solution reacted without addition of the compound wasused as a “control”, and the count of the solution without the compoundand ATP was used as a “blank”. The results of the inhibitory rate of thecompounds are shown in Table 2.

From the foregoing, it was shown that the compounds of the presentinvention strongly inhibited the activity of EGF receptor kinase.

TABLE 2 Example No. (compound No.) Inhibitory rate (%) at 1.0 μM 22 98.541 98.9 92 98.0 138 99.0 147 96.0 160 97.0

Experimental Example 3 Inhibitory Action on Breast Cancer Cell BT-474Proliferation In Vitro

A suspension of human breast cancer cell BT-474 (100 μl (6,000 cells))were sown to a 96-well microplate and cultured in an incubator (37° C.,5% carbon dioxide). On the following day, 100 μl of a solution of eachtest compound, which was previously diluted 2-fold, was added, and thecells were cultured for 5 days. After the culture medium containing thetest compound was removed, the cells were washed and fixed with 50%trichloroacetic acid, after which a 0.4% (w/v) SRB solution (dissolvedin 1% acetic acid) was added to fix and stain the cell protein (Skehanet al., Journal of the National Cancer Institute, Vol. 82, pp.1107-1112, 1990). After washing with a 1% acetic acid solution, 100 μlof an extract (10 mM Tris solution) was added to extract the pigment,and absorbance was measured at an absorption wavelength of 550 nm toquantify the amount of cells as protein content. Taking as 100% theprotein content for the control group, which received no test compoundsolution, the ratio of the residual protein content for each treatmentgroup was determined, and the compound concentration required to achieve50% suppression of the residual cell content relative to the control(IC₅₀ value) was calculated. The results are shown in Table 3.

TABLE 3 Example No. (compound No.) IC₅₀ (nM) 82 <100 92 <100 169 <100176 <100

INDUSTRIAL APPLICABILITY

According to the present invention, pyrrolo[3,2-d]pyrimidine andpyrazolo[4,3-d]pyrimidine compounds, a production method thereof and usethereof are provided. These fused pyrimidine compounds have a superiortyrosine kinase inhibitory action, are low toxic, and are sufficientlysatisfactory as pharmaceutical products.

This application is based on patent application Nos. 165050/2004 and58231/2005 filed in Japan, the contents of which are hereby incorporatedby reference.

1-29. (canceled) 30.2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanolor a salt thereof.
 31. A pharmaceutical agent comprising the compound ofclaim 30 or a salt thereof.